Document Detail

Cell signals influencing hepatic fibrosis.
Jump to Full Text
MedLine Citation:
PMID:  22973518     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Liver fibrosis is the result of the entire organism responding to a chronic injury. Every cell type in the liver contributes to the fibrosis. This paper first discusses key intracellular signaling pathways that are induced during liver fibrosis. The paper then examines the effects of these signaling pathways on the major cell types in the liver. This will provide insights into the molecular pathophysiology of liver fibrosis and should identify therapeutic targets.
Min Cong; Keiko Iwaisako; Chunyan Jiang; Tatiana Kisseleva
Related Documents :
23201728 - Effect of rhamnolipids on initial attachment of bacteria on glass and octadecyltrichlor...
10523838 - Protein kinase calpha promotes apoptotic cell death in gastric cancer cells depending u...
6861208 - Protective effects of differentiation inducers on natural killer sensitivity of k 562 c...
10397468 - Opposite effects of tpa on g1/s transition and on cell size in the low metastatic b16f1...
24571168 - Biomechanical properties of the tomato (solanum lycopersicum) fruit cuticle during deve...
11031408 - Role of cd44 variant exon 6 in invasion of head and neck squamous cell carcinoma.
Publication Detail:
Type:  Journal Article     Date:  2012-08-29
Journal Detail:
Title:  International journal of hepatology     Volume:  2012     ISSN:  2090-3456     ISO Abbreviation:  Int J Hepatol     Publication Date:  2012  
Date Detail:
Created Date:  2012-09-13     Completed Date:  2012-09-14     Revised Date:  2013-03-14    
Medline Journal Info:
Nlm Unique ID:  101564967     Medline TA:  Int J Hepatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  158547     Citation Subset:  -    
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Int J Hepatol
Journal ID (iso-abbrev): Int J Hepatol
Journal ID (publisher-id): IJHEP
ISSN: 2090-3448
ISSN: 2090-3456
Publisher: Hindawi Publishing Corporation
Article Information
Download PDF
Copyright © 2012 Min Cong et al.
Received Day: 1 Month: 3 Year: 2012
Accepted Day: 1 Month: 6 Year: 2012
Print publication date: Year: 2012
Electronic publication date: Day: 29 Month: 8 Year: 2012
Volume: 2012E-location ID: 158547
ID: 3437636
PubMed Id: 22973518
DOI: 10.1155/2012/158547

Cell Signals Influencing Hepatic Fibrosis
Min CongI1
Keiko IwaisakoI1
Chunyan JiangI1
Tatiana KisselevaI1*
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Correspondence: *Tatiana Kisseleva:
[other] Academic Editor: Michael Ott

1. Introduction

Fibrosis is the outcome of many chronic liver diseases [1], including hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease, and nonalcoholic steatohepatitis (NASH), liver intoxication (drug or nutritionally related) [1]. It is manifested by massive accumulation of the extracellular matrix (ECM) and scar formation. Several injury-triggering events play a critical role in the pathogenesis of liver fibrosis. Chronic liver injury damages the endothelial barrier and induces apoptosis of hepatocytes. Apoptotic bodies and necrotic cells release chemokines that recruit inflammatory cells to the injured liver and release fibrogenic and inflammatory cytokines (TGF-β1, IL-6, IL-1β, and TNF-α) that activate macrophages and hepatic stellate cells [2]. BM-derived and liver resident macrophages (Kupffer cells) are believed to be the major source of TGF-β1 in fibrotic liver [1, 3]. TGF-β1 is critical for the activation of fibrogenic myofibroblasts, which in response to injury upregulate α-smooth muscle actin (α-SMA) and secrete extracellular matrix proteins, mostly collagen Type I (Col), I, and III [3, 4]. Hepatic stellate cells (HSCs) contribute >80% of the myofibroblasts in the fibrotic liver in response to an hepatotoxic injury [5]. HSCs express unique markers such as Desmin and glial fibrillar acidic protein (GFAP), which distinguish them from other cells in the liver [1]. Under physiological conditions, HSCs store Vitamin A and retain a quiescent phenotype (qHSCs), but following TGF-β1 stimulation, PDGF, or matrix stiffness, or other fibrogenic stimuli they rapidly activate into type I collagen, α-smooth muscle actin expressing myofibroblasts (aHSCs) [1, 4, 6]. In addition to HSCs, cholestatic liver injury causes activation of portal fibroblasts, which differentiate into myofibroblasts and contribute to scar formation [7, 8]. Cholestatic injury also triggers cholangiocyte activation, and proliferation of the bile ducts (ductular reaction) [1].

2. Overview of the Signaling Pathways Critically Involved in Pathogenesis of Liver Fibrosis
2.1. TGF-β-Smad2/3

Signaling by the cytokine transforming growth factor-β1 (TGF-β1) plays a pivotal role in growth and differentiation, maintenance of liver homeostasis, terminal differentiation of hepatocytes and other epithelial cells, and cytokine-mediated mitogenic signaling [1, 9, 10]. The TGF-β superfamily is composed of many multifunctional cytokines, including TGF-βs 1, 2, and 3, activin, and bone morphogenic proteins (BMPs) [11, 12]. Under physiological conditions TGF-β1 regulates tissues remodeling and apoptosis to maintain cellular homeostasis [13, 14]. Under pathological conditions, TGF-β1 is the strongest known inducer of fibrosis, being a direct regulator of fibrillar collagens, TIMP1, plasminogen activator inhibitor 1 (PAI1), p300 [15]. In response to injury, TGF-β1 orchestrates a cross talk between parenchymal, inflammatory, and myofibroblast cells. Although many cells in the liver may produce TGF-β1, Kupffer cells and recruited macrophages are the major source of TGF-β1 in the fibrotic liver. TGF-β1 is critical for activation of HSCs into myofibroblasts [1]. aHSCs, and to lesser extend sinusoidal endothelial cells (ECs), also contribute to TGF-β1 production [1].

To mediate its function, TGF-β1 undergoes several important posttranslational modifications. TGF-β1 is synthesized as a nonactive proform, cleaved intracellularly by the endopeptidase furin to generate mature form, but remains biologically inactive due to its association with a complex of two proteins: latency-associated peptide (LAP) and latent TGF-β-binding protein (LTBP). This large TGF-β1-associated complex is then secreted into the ECM, where it is crosslinked by tissue transglutaminase and stored as a reservoir without any effect on the surrounding tissue [16]. Inactive TGF-β1 interacts with fibronectin. Briefly, two variations of FN exist: plasma FN (pFN), a dimeric and soluble form secreted by hepatocytes directly into the circulation; cellular FN (cFN), found in the ECM of tissues in a multimeric form containing alternatively spliced variants of extra domains EDA and EDB [17]. EDA cFN secreted by the cells or already present in the ECM activates latent TGFβ [17]. Mature TGF-β1 is released from LAP/LTBP, the latency maintaining protein complex, by activation of thrombospondin 1 (TSP-1) [18, 19], αvβ6 and αvβ8 integrins (heterodimeric matrix receptor expressed by epithelial cells, some dendritic cells, and macrophages), or acidification [16, 18, 2025]. Alternatively, TGF-β1 can be activated by several proteases such as plasmin or matrix metalloproteinases MMP-2 and 9, which directly induce degradation of the LAP/LTBP complex [26]. Neutrophil elastase, a serine protease released by neutrophil degranulation, has also been implicated in activation of latent TGF-β1 [24, 25, 27].

TGF-β mediates its biological function via signaling through the downstream molecules Smads (Figure 1). The Smad family of proteins contain a conserved Mad-homology (MH) 1 domain, an intermediate linker, and a MH2 domain [28]. There are three classes of Smads: (1) receptor-regulated Smads (R-Smads), which include Smad1, 2, 3, 5, and 8; (2) common-mediator (co-Smad) Smad4; (3) antagonistic or inhibitory Smads, Smad6 and 7 [10, 29]. Smads regulate the signals from the receptors for TGF-β superfamily members to the nucleus. Catalytically active TGF-β type I receptor (TβRI) and activin type I receptor (ActRI) phosphorylate serine residues of receptor-activated Smad2 and Smad3 [30]. Smad proteins have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β Type I receptors differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L), or dually (L/C) phosphorylated (p) isoforms. Although COOH-tail phosphorylation by TβRI is a key event in R-Smad activation, additional phosphorylation can positively and negatively regulate R-Smads pathway. Thus, the linker domain undergoes regulatory phosphorylation by JNK and cyclin-dependent kinase (CDK) pathways [31].

Activated Smad2/3 complex forms hetero-oligomers with Smad4. In association with Smad4, the Smad2/3 complex is translocated to the nucleus, where it initiates transcription of TGF-β1 target genes. This pathway is regulated by several autoinhibitory feedback loops, for example, Smad7, Ski, SnoN, and Bambi are negative regulators of TGF-β1 signaling [22, 32].

Studies of genetically altered mice have demonstrated the importance of TGF-β1 signaling pathway for development of fibrosis. Overexpression of TGF-β1 in transgenic mice results in fibrosis of multiple organs [1], and TGF-β1−/− mice strongly attenuate the development of liver fibrosis [1, 33, 34]. Consistently, Smad3−/− mice, which lack the Smad3 signaling molecule downstream of TGF-β1, are much less susceptible to liver fibrosis than wild type mice [24, 25, 35]. The role of Smad2 in fibrosis is less well characterized due to the lethal phenotype of Smad2−/− mice, but in comparison with Smad3, seems to regulate a distinct set of target genes [36]. TGF-β signaling can also be mediated by noncanonical, “non-Smad,” signaling pathways, triggered by phosphorylation of the Smad linker region [37] or by recruitment of other proteins, such as MAPK, PP2A/p70S6K, RhoA, and TAK1/MEKK1 to the activated TGFβ receptor complex without a direct effect on Smad activation [37, 38].

2.2. NFκB

Nuclear factor κB (NFκB) is a key transcription factor involved in a broad range of biological processes, including immune responses, cell survival, stress responses, and maturation of various cell types [39]. NFκB is composed of hetero- or homodimers formed by the Rel protein family (p65, p50, p52, c-Rel, and RelB), all containing the Rel homology domain (RHD) [40, 41]. The canonical p65 : p50 heterodimer is the most abundant dimer in NFκB signaling pathway [40, 41]. Generation of each monomer is transcriptionally regulated, but p50 and p52 are also regulated by processing of precursor proteins p105 and p100, respectively [39].

The functional activity of NFκB is determined by its natural stoichiometric inhibitors IκBs [40, 41]. The classical inhibitor proteins in the NFκB signaling system consist of the single polypeptide IκBs: IκBα, IκBβ, and IκBε, characterized by their ankyrin repeat domain (ARD) [40, 41]. In resting cells, IκB binds the NFκB dimer and prevents its nuclear translocation and DNA binding. IκBα is the most common inhibitor, which directly interacts with NFκB to form inactive complexes residing in the cytoplasm. Following cytokine stimulation, activation of the IκB kinase (IKK) in turn induces phosphorylation, ubiquitination and subsequent IκBα degradation, releasing active NFκB [42] (Figure 2). Released NFκB translocates to the nucleus where it initiates transcription of NFκB target genes via direct binding to NFκB-specific DNA motifs (GGGRNNYYCC, where R is purine, Y is pyrimidine, and N is any base). Interestingly, IκBα itself is one of the NFκB target genes [40, 41]. Synthesis of other members of the IκB family is also dependent on NFκB activity via negative feedback. Subsequent studies have suggested that there are two pathways of NFκB activation [39]. The canonical NFκB pathway is defined as being mediated by a NEMO-dependent kinase IKK (IKKγ) activation; while the noncanonical pathway is NEMO-independent kinase complex involving IKKα (IKK1) and the NFκB-inducing kinase (NIK) [43]. In the canonical pathway, preexisting, latent NFκB dimers are released from classical IκBs. In the noncanonical pathway, new synthesis of p100 and RelB allows for generation of RelB : p52 which is insensitive to IκB control and thus translocates to the nucleus [39].

The importance of these findings has been confirmed using knockout mice. Thus, deletion of NEMO (IKKγ) resulted in embryonic lethality in mice caused by a massive apoptosis in the fetal liver [44]. Similar to that, the IKKβ (IKK2) knockout [45] and the RelA knockout [46] have a lethal phenotype, suggesting that all these proteins are involved in one signaling axis of NEMO-IKKβ-RelA. IKKα may compensate for the loss of IKKβ (IKK2) [47]. Moreover, studies of genetically deficient mice demonstrate an essential role of the noncanonical NFκB pathway in various biological processes, including regulation of developmental signals. Thus, mice lacking RelB−/−, NfκB2−/−, and NIK−/− have defective development of lymph nodes and Peyer's Patch [39, 48, 49].

2.3. LPS-TLR4

Liver fibrogenesis is associated with increased intestinal permeability [1]. Bacterial products, including lipopolysaccharide (LPS, cell walls of gram-negative bacteria), signal via Toll-like receptor pathways. Toll-like receptors (TLRs) are innate immune signal receptors which recognize pathogen-associated molecular patterns (PAMP) such as LPS, peptidoglycan, and bacterial derived unmethylated CpG-DNA. In addition, endogenous ligands (alarmins) can bind TLR4 in the presence of CD14 and LPS binding protein (LBP) and transduce similar signals [50]. Thus, endogenous ligand HMGB-1, hyaluronan, and products of dying cells have been shown to trigger TLR signaling. LPS binds to TLR4 with its coreceptors MD-2 and CD14 and transmits its signal through adaptor proteins MyD88, TIRAP, TRIF, and TRAM to activate the kinases, IRAK1, IRAK4, TAK1, JNK, and IKK (Figure 3). These intracellular kinases lead to the activation of the transcription factors NFκB, AP-1, and interferon regulatory factors (IRFs), resulting in the induction of potent innate immune responses [3, 51]. Upon activation of TLRs, cells produce proinflammatory cytokines, such as TNF-α, IL-6, IL-1, MCP-1, and RANTES [50].

Using TLR4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, Seki et al. have shown that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor TGF-β1 pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells [3].

TLRs are critical in liver fibrosis [3, 52]. Patients with hepatic cirrhosis have elevated portal vein levels of LPS. Portal hypertension can damage the intestinal mucosa compromising its barrier function and trigger bacterial translocation. The liver has a unique vascular system within the gastrointestinal tract, as the majority of the liver's blood supply comes from the intestine through the portal vein. When the intestinal barrier function is disrupted, an increase in intestinal permeability leads to the translocation of intestine-derived bacterial products such as lipopolysaccharide (LPS) and unmethylated CpG containing DNA to the liver via the portal vein. These gut-derived bacterial products stimulate innate immune receptors, namely Toll-like receptors (TLRs), in the liver. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes. TLRs activate these cells to contribute to acute and chronic liver diseases [5356]. Therefore, LPS derived from the intestinal microflora is a strong candidate for the TLR4 ligand in hepatic fibrosis [57]. Consistently, gut sterilization with antibiotics attenuates liver fibrosis, and pathogen free animals are resistant to liver fibrosis [3]. Mice with deficiencies in components of TLR4 signaling pathway, CD14, LPS binding protein (LBP), or TLR4 have impaired TLR signaling and are less susceptible to liver fibrosis [58].

In addition, fragments of fibronectin have been implicated in physiological and pathological processes, especially tissue remodeling associated with inflammation [17]. Cellular fibronectin containing an alternatively spliced exon encoding type III repeat extra domain A (EDA) is produced in response to tissue injury [59, 60]. EDA-containing fibronectin fragments produce cellular responses similar to those provoked by bacterial lipopolysaccharide (LPS). EDA-containing fibronectin binds to and activates TLR4 [60], inducing nuclear translocation of nuclear factor NFκB [61].

2.4. Stat3 Signaling

The Janus kinase-signal transducers and activators of transcription (Jak-Stat) signaling pathways are activated in the liver by more than 20 cytokines and growth factors and play a critical role in a variety of cellular functions, such as antiviral defense, acute phase response, hepatic injury, repair, inflammation, transformation, and hepatitis [62, 63]. Stat3 was originally identified as an acute-phase response factor, activated by IL-6 and other cytokines [64], but has been implicated in cellular transformation and carcinogenesis [65]. Stat3 is expressed in most tissues and early during postimplantation. Consistent with this, disruption of the Stat3 gene leads to an early embryonic lethal phenotype [66]. Tissue specific Stat3 knockouts have been generated using floxed alleles. Stat3 deficient T cells exhibit a lower proliferative response to IL-6, which suppresses apoptosis in these cells [67]. Stat3 deleted macrophages (and neutrophils) have aberrant IL-10 signaling and immune regulation [68]. Stat3 null mammary gland epithelial cells exhibit a delay in programmed cell death that occurs during cyclical gland involution [69]. Mice with Stat3-deficient hepatocytes exhibit defects in their ability to induce acute phase response genes (e.g., serum amyloid protein (SAP), fibrinogen (FB), haptoglobin (HP), serum amyloid A protein (SAA), and hemopexin (Hpx) in response to IL-6 [70]. In addition, Stat3 signaling in hepatocytes provides antiapoptotic cytoprotection [71]. Deletion of this pathway abolishes the induction of the acute-phase response, leading to more severe cholestasis and an enhanced inflammatory response with increased TNF-α expression and subsequent cytotoxicity [71].

Cytokine signaling plays a pivotal role in the pathogenesis of liver fibrosis, which was assumed to be linked to deregulation of Th1/Th2 homeostasis towards Th2 responses [72]. However, expression of profibrogenic cytokines does not always correlate with the Th1/Th2 classification. Thus, despite driving a Th2 response, IL-6 and IL-10 have antifibrogenic effects (Figure 4). Hepatic fibrosis was increased in IL-6−/− mice and in IL-10−/− mice due to the loss of hepatocyte protection [7375]. IL-22, a member of the IL-10 family of cytokines, also signals via the Jak2-Stat3 pathway and mediates hepatocyte survival during liver injury [76, 77].

3. Signaling Cascades Activated in Different Cell Types During Liver Fibrogenesis
3.1. Hepatocytes

Hepatocytes contribute to 80% of liver mass. Hepatocytes play a critical role in metabolism and detoxification for the organism [78] and are the major storage of glycogen. In the normal adult liver, mature hepatocytes exhibit a quiescent phenotype, stay in the G0 phase of the cell cycle, and show minimal turnover. However, upon hepatocyte loss (such as toxic liver injury, infection, or surgical resection), these mature hepatocytes proliferate, while maintaining their metabolic function. Hepatocyte function is heterogeneous, in part due to their location within the acinus [79, 80]. For example, while pericentral hepatocytes (adjacent to the central vein) express glutamine synthase, ornithine aminotransferase, and thyroid hormone receptor β1, periportal hepatocytes (adjacent to the portal triad) upregulate HNF-α and convert ammonia to urea [81, 82].

3.1.1. TGF-β-Smad2/3 Signaling

TGF-β signaling in hepatocytes is implicated in negative regulation of the growth response. TGF-β type I receptor (TβRI) differentially phosphorylates COOH-tail serine residues of receptor-activated Smad (R-Smad, which include Smad2 and Smad3 to create three phosphorylated forms (phosphoisoforms) [30]: COOH-terminally phosphorylated R-Smad (pSmad2C and pSmad3C), linker-phosphorylated R-Smad (pSmad2L and pSmad3L), and dually phosphorylated R-Smad (pSmad2L/C and pSmad3L/C) [9, 83, 84]. While pSmad2L resides in the cytoplasm, the other phosphoisoforms are localized to cell nuclei [31]. In homeostasis, TGF-β-mediated pSmad3C signaling in hepatocytes opposes proliferative responses induced by mitogenic signals, causing arrest of cell cycle progression in the G1 phase by downregulation of c-Myc and induction of p21WAF1 [28, 85]. Acute liver injury induces secretion of proinflammatory cytokines, as well as TGF-β and activin A [9]. In turn, the loss of liver parenchyma triggers proliferation of resting hepatocytes. Even though TGF-β and activin concentrations are elevated, mitogenic proinflammatory cytokines regulate liver regeneration by shifting from cytostatic pSmad3C signaling to mitogenic pSmad3L signaling. This phenomenon allows hepatocytes to acquire “temporary resistance” to TGF-β (and activin A) and proliferate during liver regeneration [86, 87]. Inflammatory cytokine-induced pSmad3L stimulates c-Myc transcription [88, 89], which increases the proliferation of regeneration of hepatocytes and suppresses the cytostatic action of the pSmad3C/p21WAF1 pathway [9].

TGF-β-Smad2/3 signaling in hepatocytes has also been implicated in epithelia-to-mesenchymal transition (EMT), a process in which fully differentiated epithelial cells undergo phenotypic transition to fully differentiated mesenchymal cells (fibroblasts or myofibroblasts) [90]. During EMT, epithelial cells detach from the epithelial layer, lose their polarity, downregulate epithelial markers (e.g., hepatocyte marker albumin, cytokeratins, cadherins) and tight junction proteins (zonula occludens-1, ZO-1), increase their motility, and obtain a myofibroblast phenotype [91], with upregulated expression of α-smooth muscle actin (SMA) and vimentin in EMT-originated myofibroblasts. Epithelial cells transitioning into myofibroblasts are also reported to express fibroblast specific protein-1 (FSP1, S100A4), which is used as a marker of EMT in fibrogenesis and cancer [9194]. Hepatocytes have been implicated in EMT in response to liver injury [95], suggesting that mature hepatic epithelial cells can contribute to fibrogenic myofibroblasts and collagen production in response to injury. EMT has been originally described during embryonic development [91] and plays a critical role in TGF-β-induced organogenesis. However, the role of EMT in fibrogenic disease has been recently questioned [96]. Studies based on the genetic labeling of hepatocytes, using Albumin-Cre mice, have demonstrated that hepatocytes are capable of differentiating into myofibroblasts in vitro, but not in vivo [97]. Moreover, FSP1 is not a robust marker for EMT, since its expression is not restricted to EMT-transitioning cells, but is expressed by myelomonocyic lineage cells [98100].

TGF-β induces expression of growth factors and cytokines by hepatocytes. Moreover, hepatocytes serve as a significant source of BMP-7, a natural inhibitor of the TGF-β1-signaling pathway belonging to the TGF-β superfamily. Administration of BMP-7 in pharmacological doses attenuates the development of kidney fibrosis and liver fibrosis [101103]. Hepatocyte-specific deletion of Smad7 results in spontaneous liver dysfunction and aggravation of alcohol-induced liver injury [104].

3.1.2. LPS-TLR4 Signaling

Consistent with their filtering/detoxification function, hepatocytes express TLRs which are constitutively engaged by bacterial products in the liver [105]. Primary cultured hepatocytes express mRNA for all TLRs, but are capable of responding only to TLR2 and TLR4 ligands in vitro. However, TLR2 and TLR4 signaling in hepatocytes is fairly weak in vivo [106108]. Under inflammatory conditions, hepatocytes upregulate TLR2 and become more sensible to TLR2-mediated signals. At the same time, TLR4 expression in hepatocytes is not strongly upregulated [109]. Although hepatocytes express TLR4 and are capable of transmitting TLR4 signals in vitro, the contribution of TLR4 signaling in hepatocytes is limited. Meanwhile, the TLR/MyD88-mediated pathway is required for the initiation of liver regeneration after partial hepatectomy (PH) [108, 110].

3.1.3. TNF-α-NFκB

Chronic injury causes an imbalance between the production of protective and damaging cytokines, resulting in the activation of apoptotic signals in hepatocytes. TNF-α and related cytokines play a key role in mediating hepatocyte homeostasis by regulating both anti- and proapoptotic pathways. TNF-α signals through TNF-R1 and TNF-R2, of which TNF-R1 plays a critical role in TNF-α-mediated activity in the liver. The proapoptotic effects of TNF-α result from a cascade of caspase activation. This pathway is initiated by TNF-α-induced TNF-R1 receptor crosslinking, recruitment of TRADD and FADD (adaptor protein TNF receptor TRADD and Fas-associated death domain FADD) and cleavage of caspase 8, which activates the downstream proapoptotic caspases (caspases 3, 6, 7). In turn, the activation of TNF-α-dependent prosurvival signals is mediated by NFκB activation and involves transcriptional expression of suppressors of apoptosis, including Bcl-2, Bcl-xL, and Bfl-1 [111]. However, TNFα also activates NFκB, rendering hepatocytes resistant to apoptosis unless also treated with cycloheximide, actinomycin D or the super-repressor of IκB [112, 113].

3.1.4. IL-6-Stat3 Signaling

In hepatocytes, IL-6 plays a crucial role in liver regeneration and transmits its mitotic signals mainly through Stat3. IL-6 stimulates hepatocytes to produce acute-phase response proteins, including serum amyloid A, complement C3 and C-reactive protein. In IL-6-deficient mice, Stat3 activation is dramatically suppressed in hepatocytes [80]. Although Stat3 signaling can be induced by other cytokines, such as G-CSF [114] and leptin [115], current data suggests that Stat3 in hepatocytes is almost exclusively activated by IL-6. Thus, hepatocyte regeneration in response to partial hepatectomy triggers activation of the IL-6/Stat3 signaling pathway, composed of IL-6 receptor, gp130, receptor-associated Janus kinase (Jak), and Stat3. The IL-6 receptor forms a complex with two molecules of gp130 [62].

Stat3 promotes liver regeneration by promoting cell cycle progression from G1 to S phase [116]. Stat3 regulates the expression of cyclin D1 [117], which is required for hepatocyte proliferation [118]. As expected, hepatocyte-specific Stat3-deficient mice exhibit impaired DNA synthesis and mitotic activity of hepatocytes after partial hepatectomy.

Other target genes of Stat3 include antiapoptotic genes FLIP, Bcl-2, and Bcl-xL [118, 119]. Therefore, it is believed that Stat3 prevents liver damage by its antiapoptotic and promitogenic effects [78]. Deletion of the gp130/Stat3 pathway in hepatocytes leads to increased hepatotoxicity and accelerates liver injury and inflammation [71]. This effect is likely mediated via the Stat3 induction of EGFR and IGF-1 signaling pathways [120]. Interestingly, Stat3 also possesses antioxidative capacity. Hypoxia and reperfusion injures hepatocytes via the generation of reactive oxygen species (ROS) and activation of redox-sensitive caspases such as caspase-3/-9. Stat3 upregulates Ref-1 [121] and Mn-SOD [122], which protects hepatocytes from ROS-mediated apoptotic cell death [118]. Thus, activation of Stat3 in hepatocytes has hepatoprotective and anti-fibrotic effects [123].

3.2. Kupffer Cells

Kupffer cells are liver-resident macrophages, which are long lived and radiation resistant. They express myeloid markers such as F4/80, CD68, CD11b, CCR2, and CX3CR1 [51, 124, 125]. However, there are currently no specific markers distinguishing Kupffer cells from recruited BM derived macrophages. It is believed that both of these populations actively participate in development of liver fibrosis by secretion of TGF-β1, IL-6 and other profibrogenic cytokines.

3.2.1. TLR Signaling

Kupffer cells are well established targets for the TLR4 ligand LPS and produce inflammatory and fibrogenic cytokines, which may activate HSCs [126]. However, TLR4 signaling in Kupffer cells is not critical for the pathogenesis of experimental liver fibrosis. Deletion of TLR4 signaling in BM-derived inflammatory cells and Kupffer cells was achieved in BM-chimeric mice, pretreated with clodronate (to reconstitute long-lived Kupffer cells). Interestingly, only a modest inhibition of liver fibrosis was observed in these mice in response to liver injury [3, 51]. However, LPS, but not TGF-β, is a strong activator of Kupffer cells in vitro and in vivo. LPS-stimulated Kupffer cells secrete TNF-α and TGF-β. Furthermore, experimental alcoholic liver disease requires TLR4 on BM derived macrophage and Kupffer cells [51, 127]. Interestingly, only a modest inhibition of liver fibrosis was observed in these mice in response to liver injury. These results indicate that LPS-induced fibrosis does not need Kupffer cell-mediated activation of HSC.

3.2.2. IL-6-IL-10-Stat3 Signaling

IL-6 and IL-10 induce opposing effects on macrophages. IL-6 signals via gp130 and IL-6R and promotes inflammatory responses in Kupffer cells/macrophages. In turn, IL-10 secreted by Th1 and T cells stimulate IL-10R1 and IL-10R2 on Kupffer cells/macrophages, causing their prolonged activation. Activation of IL-10-Stat3 signaling inhibits inflammatory responses. Stat3 upregulates expression of the suppressor of cytokine signaling 3 (SOCS3) [128], which binds to gp130, limiting IL-6-induced inflammatory responses [78]. Thus, while IL-6 triggers proinflammatory responses in macrophages, IL-10 mediates anti-inflammatory responses that are associated with decreased liver fibrosis [78, 128].

3.3. Endothelial Cells

Liver sinusoidal endothelial cells (LSECs) maintain the integrity of hepatic sinusoids and mediate barrier function, blood clearance, vascular tone, immunity, hepatocyte growth, and injury-induced angiogenesis [129131]. LSECs differ from other ECs by the lack of basement membrane and together with hepatic stellate cells HSCs (residing in the space of Disse and acting as pericytes in the normal liver), form a fenestrated monolayer which regulates the blood supply to underlying hepatocytes [1]. Regulation of hepatic vascular tone is mediated by HSC contractility mediated by endothelin-1, angiotensin II, norepinephrine, prostaglandin F2, thromboxane A2, and thrombin [1, 132]. Disruption of the integrity of the endothelium results in defenestration and capillarization of LSECs, and activation of an antifibrinolytic cascade to support coagulation and hemostasis [133]. In turn, LSECs secrete cytokines and soluble factors (such as monocyte chemoattractant protein 1 (MCP-1) and endothelin-1(ET-1)) that induce recruitment of inflammatory cells, contractility of HSCs, and platelet aggregation and degranulation [129]. In turn, as a part of a wound healing process, LSECs proliferate and migrate. In response to chronic injury, numerous mediators of angiogenesis, including angiopoietins, transforming growth factor (TGF-β1), platelet-derived growth factor (PDGF), tumor necrosis factor-alpha (TNF-α), interleukins, and members of the fibroblast growth factor family (FGF), are produced [134]. However, vascular endothelial growth factor (VEGF) remains the strongest inducer of angiogenesis [135].

Damage to the hepatic endothelium is further increased by portal hypertention and NO production, which accompany fibrogenic liver injury. NO production increases vasodilation and permeability of LSECs. Dysfunctional LSECs contribute to local production of NO production, further facilitating liver injury [10, 133].

3.3.1. Angiotensin 1 and VEGF

VEGF is an important regulator of angiogenesis and vascular tone. VEGF controls LSEC survival, proliferation, migration, and angiogenesis. VEGF binds to the receptor VEGFR2 and mediates its biological responses through reactive oxygen species (ROS) [136]. Another strong angiogenic factor, Angiopoietin 1 (Ang 1), regulates maturation and stability of blood vessels. Moreover, neovascularization induced during the development of livers fibrosis is mediated by Angiopoietin 1, expressed mostly by activated HSCs [137]. In turn, Ang 1 signals through endothelial receptor tyrosine kinase Tie2 and synergistically enhances VEGF's effects [138]. VEGF binds to its receptor and activates an Akt signaling cascade to increase vascular tone and the formation of collateral circulation [139, 140].

Furthermore, proliferation and migration of endothelial cells depends on pericyte coverage of vascular sprouts for vessel stabilization. This process is regulated by VEGF and platelet-derived growth factor (PDGF) through their cognate receptors [141]. VEGFR is expressed on endothelial cells, and PDGFR is expressed on HSCs and vascular smooth muscle cells (VSMCs). Moreover, it is believed that PDGF-Rβ is exclusively expressed by HSCs in the liver and strongly upregulated in HSCs in response to fibrogenic liver injury [1]. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators. VEGF acts as a negative regulator of neovascularisation. Specifically, while pericyte-derived PDGF mediates angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. VEGF-mediated activation of VEGF-R2 suppresses PDGF-Rβ signaling in HSCs/pericytes/VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rβ and VEGF-R2 [141]. Thus, VEGF ameliorates development of liver fibrosis and can serve as a novel target for anti-fibrotic therapy [142].

3.3.2. TGF-β-Signaling

TGF-β signaling in endothelial cells plays a critical role in vascular development and maintenance of vascular homeostasis. Mice deficient for various TGF-β signaling components have an embryonic lethal phenotype due to vascular defects, abnormal yolk sac vasculogenesis and/or angiogenesis [143, 144]. TGF-β is also essential for vascular integrity in the adults due to its role in regulation of anti-inflammatory characteristics of endothelial cells, growth and migration [145]. Similar to other cell types, TGF-β signaling in endothelial cells results in activation of TGF-β receptors with Ser/Thr kinase activity. The effect of TGF-β on endothelial cells is dose-dependent. Low levels of TGF-β promote angiogenesis, while higher doses inhibit angiogenesis [146]. TGF-β regulates the activation of the endothelium via two opposing type I receptor/Smad pathways, activin receptor-like kinase (ALK)1 and ALK5 [145]. The classical TGF-β type I receptor that activates Smad2/3 signaling is ALK5 (TGFβ-RI). ALK2 (ActRI) is typically used by BMPs to activate Smads1/5/8. Use of ALK2 by TGF-β is rather an exceptional nonhepatic event [147]. Typically the Smad2/3 pathway is activated by the type I receptors ALK4, 5 or 7 [28]. Furthermore, a coreceptor of TGF-β, endoglin (CD105), is upregulated on proliferating endothelial cells and facilitates effective TGF-β-ALK1 signaling [148, 149]. Another molecule which regulates TGF-β signaling is VE-cadherin. VE-cadherin-deficient endothelial cells demonstrate a loss of TGF-β-induced inhibition of endothelial cell proliferation and motility [145, 150].

TGF-β signaling in endothelial cells may contribute to fibrosis via transition to mesenchymal cells (EndMT), giving rise to myofibroblasts in response to fibrogenic injury. EndMT has been reported to contribute to cardiac [151] and renal [152] fibrosis. The generation of mesenchymal profibrotic cells from endothelial cells by this process appears to recapitulate the transdifferentiation of endothelial cells that leads to the formation of the cardiac valves in embryonic development [153]. EndMT is identified by expression of myofibroblasts-like genes [91] in endothelial cells that are expressing or have a “history” of expressing PECAM-1/CD31, Tie-1 [151], Tie-2 and CD34 [152, 154]. A difficulty in interpreting these studies is that it is now recognized that Tie-2 is not a specific marker for endothelial cells in that it is also expressed in BM derived hematopoietic cells. Although endothelial cell injury [10] and neovascularization play a critical role in liver fibrosis, the role of EndMT in liver fibrosis is unknown.

3.3.3. TLR4-Signaling

LSEC are exposed to endogenous LPS liver injury. LPS induces upregulation of TLR4 expression in LSECs to facilitate angiogenesis [131]. In vitro, this effect is dependent on Myd88 activation and is associated with secretion of MMP2 by LSEC. In vivo studies have supported this data, demonstrating that TLR4-deficient mice exhibit attenuated angiogenesis and fibrosis [155].

Low, physiological concentrations of endotoxin are continuously present in portal venous blood, and the liver mediates intrinsic signals to develop tolerance [155]. LPS induces the release of IL-10 from LSECs and Kupffer cells and also downregulates CD4+ T cell activation by LSECs through down-modulation of the expression of MHC class II, CD80 and CD86. In contrast, TLR4 activation of professional APC by endotoxin increases T cell activation. These observations explain why the tolerogenic effect in the liver seems to be related to the continuous exposure of sinusoidal cells to bacterial products from the gut (reviewed in [155]). Following initial activation of LSECs, Kupffer cells are a tolerogenic cellular population contributing to the tolerogenic properties within the liver [155].

3.3.4. TNF-α-NFκB

In response to liver injury, release of endogenous LPS mediates release of TNF-α, which in turn triggers expression of target genes in LSECs. However, a specific role of NFκB in LSECs in the pathogenesis of liver fibrosis has not been evaluated [156]. Experiments in transgenic mice overexpressing the IkB-α super-repressor in endothelial cells, have demonstrated that inhibition of the NFκB signaling pathway in LPS-stimulated mice causes a defect in expression of endothelial tight junction proteins, and as a result, a loss of integrity of the endothelium and increased vascular permeability [157], suggesting that NFκB is responsible for the stress-induced responses of the endothelium to septicemia or TNF-α.

3.3.5. Stat3

The role of Stat3 in endothelial cells has not been carefully studied. It has been suggested that Stat3 facilitates protection of endothelial cells (LSEC) exposed to endogenous LPS liver injury and inflammation. IL-6 has a protective effect on hepatic LSECs by activation of Stat3 signaling [158160]. Consistent with this, endothelial-specific Stat3-deficient mice are more susceptible to alcohol-induced injury, demonstrating a critical function of the endothelium and LSECs in chronic liver injury [160]. Recent study has implicated Stat3 signaling in endothelial cells in mediating dual anti-inflammatory and antiapoptotic functions, of attenuating hepatic inflammation and SEC death during alcoholic liver injury [161].

3.4. Cholangiocytes

Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, are ciliated cells. Each cholangiocyte has a primary cilium consisting of a microtubule-based axoneme and the basal body, centriole-derived, microtubule-organizing center from which the axoneme emerges. Cholangiocyte cilia extend from the apical plasma membrane into the bile duct lumen [162]. Cholangiocytes, the biliary epithelial cells, can be identified by their apical structure and expression of specific keratins, such as K-19 [163]. Cholangiocytes originate from the common epithelial progenitor in the liver during development. Unlike hepatocytes, they lack the ability to regenerate their mass [164]. However, cholangiocytes are capable of proliferation in response to cholestatic liver injury, and this phenomenon has been referred as the ductular reaction [1]. It is believed that cholangiocytes participate in the activation of portal fibroblasts, located in close proximity. Cholangiocytes have been implicated in secretion of a variety of cytokines and factors, which accelerate development of liver fibrosis [165], including NGF, MCP-1 growth factors HGF, VEGF, CTGF, and endothelin-1 [166]. However, it remains unclear if cholangiocytes serve as a significant source of cytokines.

3.4.1. TGF-β-Smad

Difficulties associated with the isolation and culturing of a pure population of cholangiocytes is a limiting factor in investigating the role of cholangiocytes in fibrogenic liver injury. It has been suggested that similar to hepatocytes, cholangiocytes are capable of differentiation into fibrogenic myofibroblasts via epithelial-to-mesenchymal transition (EMT) in response to TGF-β-induced liver injury [167, 168]. Although EMT in hepatocytes has been documented in vitro, in vivo studies in adult mice using Cre-lox-based cell fate mapping have not confirmed this finding [97]. Similarly, genetic labeling of K19+ cholangiocytes has demonstrated that cholangiocytes do not contribute to fibrogenic myofibroblasts in experimental cholestatic liver injury [163, 169]. Moreover, hepatic epithelial cells and their precursors, genetically labeled in alpha-fetoprotein-Cre mice, do not differentiate into fibrogenic myofibroblasts in adult mice [96, 170].

3.4.2. TLR Signaling

A few studies have mostly linked TLR signaling in cholangiocytes to anti-microbial immunity [171, 172]. Cholangiocytes may participate in microbe-associated, hepatic proinflammatory responses. In vitro studies of cultured human cholangiocytes suggest that LPS-TLR-signaling pathway activate the small GTPase Ras that mediates cholangiocyte proinflammatory cytokine production and proliferation [172].

3.4.3. NFκB and Stat3 Signaling Pathways

NFκB and/or Stat3 signaling pathways in cholangiocytes have not been specifically evaluated. Meanwhile, conditional inactivation of Stat3 in hepatocytes and cholangiocytes (stat3(Deltahc) of multidrug resistance gene 2 mdr2(−/−) mice strongly aggravated bile acid-induced liver injury and fibrosis [120].

3.5. Hepatic Stellate Cells

HSCs are perisinusoidal cells that normally reside in the space of Disse and contain retinoid lipid droplets [173, 174]. Under physiological conditions, HSCs exhibit a quiescent phenotype and express neural markers, such as glial fibrilar acid protein (GFAP), synemin, synaptophysin [1], and nerve growth factor receptor p75 [175, 176], secrete hepatocyte growth factor (HGF), and store vitamin A [177]. HSCs are also implicated in phagocytosis and antigen presentation [178, 179]. In response to injury, HSCs have decreased lipid droplets, acquire contractility, and activate into collagen type I+α-SMA+ myofibroblasts. During development HSCs are derived from the translocation of submesothelial mesenchymal cells from the liver capsule [180].

3.5.1. TGF-β-Smad2/3 Signaling

TGF-β signaling plays a critical role in initiating and promoting the activation of qHSCs into myofibroblasts. Nuclear localization of pSmad2 and pSmad3 is seen in the activated HSC [9]. Transgenic mice have demonstrated that overexpression of TGF-β produces liver fibrosis [181], and conditional induction of TGF-β has demonstrated that the severity of fibrosis is proportional to the level of produced TGF-β [24]. Smad3 is a direct mediator of matrix production in aHSCs. Mice lacking Smad3 are protected from fibrosis [25, 182]. Activation of TGF-β signaling causes transient expression of Smad7, regulated by a feed-back mechanism. Smad7, in turn, inhibits HSC differentiation into fibrogenic myofibroblasts and attenuates experimental fibrosis in vivo [183, 184]. BMP-7, another member of the TGF-β superfamily, also acts as a TGF-β antagonist and administration of BMP-7 in pharmacological doses attenuates development of kidney and liver fibrosis [101103].

Although activation/phosphorylation of Smad2/3 is considered to be the main fibrogenic pathway in HSCs, TGF-β1 has been also found to mediate its profibrogenic action via an alternative ALK1/Smad1 pathway in HSCs by upregulation of Id1 (the inhibitor of differentiation (1) that facilitates HSC activation [185]. TGF-β1 controls the transdifferentiation process in HSCs. The recent study, aimed to elucidate TGF-β1 target genes responsible for fibrogenesis, has analyzed the Smad7-dependent mRNA expression profiles in HSCs, and identified that Id1 protein was strongly reduced by ectopic Smad7 expression in HSCs. In concordance, Id1 overexpression in HSCs enhanced cell activation, while knock-down of Id1 in HSCs inhibited HSC differentiation into myofibroblasts. Treatment of HSCs with TGF-β1 resulted in Id1 upregulation implicating Id1 to be an alternative but critical mediator of HSC activation into myofibroblasts signaling via TGF-β1/ALK1/Smad1 pathway [185].

Other factors can facilitate TGF-β signaling in HSCs. In particular, stimulation of aHSCs with platelet-derived growth factor (PDGF) and TGF-β produces a synergistic effect on migration and expression of MMPs [186, 187]. Moreover, PDGF promotes the activation of HSCs via activation of the PI3K-Akt signaling pathway. PI3K (phosphatidylinositol-3-kinase) activity phosphorylates PIP2 to generate PIP3 (3,4,5-trisphosphate) [188]. PIP3 binds to the pleckstrin homology domain of Akt, directing it to the cell membrane where it becomes activated by phosphorylation events to initiate cell survival mechanisms. Consistently, inhibition of PI3K activity suppresses cell proliferation and type I collagen gene expression in activated HSCs [189, 190]. PDGF also activates ERK in HSCs by sequential activation of Ras-Raf-MEK signaling [191] and further facilitates proliferation of aHSCs [192].

The tumor suppressor protein phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a dual specificity protein and lipid phosphatase that dephosphorylates PIP3 [188, 193]. PTEN is a negative regulator of PI3K and ERK signaling [190]. Overexpression of PTEN attenuates collagen Type I production when aHSCs induces HSC apoptosis. Deletions of PTEN occur during malignant transformation in various tissues [193]. Decreased PTEN expression is also associated with dysregulation of tissue remodeling, such as pulmonary fibrosis, bronchial asthma, and rheumatoid arthritis [194196]. Since the PI3K/Akt pathway stimulates proliferation and activation of HSCs, inhibiting PTEN promotes liver fibrosis [197].

3.5.2. PDGF Signaling

Platelet-derived growth factor (PDGF) is a powerful mitogen for HSCs. In fibrotic liver, PDGF induces HSC proliferation, synergistically facilitating TGF-β1-mediated HSC activation [192]. PDGF signals through the transmembrane receptor tyrosine kinases initiating multiple signaling pathways [198, 199], including activation of the mitogen-activated protein kinase (MAPK) family implicated in cellular proliferation and transmigration. This includes the extracellular signal-regulated protein kinase (ERK) pathway and two stress-activated protein kinase (SAPK) pathways: the c-Jun N-terminal kinase (JNK) and the p38 pathway [31].

3.5.3. TLR4-Signaling

LPS activates the NFκB and JNK/AP-1 pathways in aHSCs. LPS enhances expression of the adhesion molecules ICAM-1 and VCAM-1 and TLR2 and the secretion of IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, KC, MIP-2, and IP-10 in aHSCs. In turn, LPS downregulates the expression of bone morphogenetic protein (BMP) and activin membrane bound inhibitor (Bambi), a transmembrane suppressor of TGF-β signaling (Figure 5). Bambi is a TGF-β pseudoreceptor that lacks an intracellular kinase domain, and similar to activin, prevents TGF-β signaling. Signaling via TLR4 downregulates Bambi and facilitates TGF-β signaling in HSCs. Overexpression of Bambi inhibits HSC activation, while overproduction of a dominant negative form of Bambi enhances TGF-β signaling, and induces activation of HSCs [51].

LPS signaling is blocked by inactivation of NFκB and JNK, demonstrating the role of NFκB and JNK in TLR4 signaling in HSCs. TLR4 signaling in HSCs is critical for development of liver fibrosis. Bone-marrow chimeric mice with a TLR4 deficiency in recipient liver cells, including HSCs, were resistant to liver fibrosis. Since hepatocytes exhibited no response to LPS in vivo, HSCs were proposed to be the major cell population in the injured liver transmitting TLR4-induced fibrogenic signals [3].

3.5.4. NFκB

TNF-α has a dual role in HSC biology. TNF-α can produce antiapoptotic (via NFκB activation), or proapoptotic (via caspase activation) and antiproliferative responses in HSC [113, 200]. The later effect is mainly attributed to the ability of TNF-α to regulate CD95L expression.

Activation of HSCs in response to fibrogenic liver injury is associated with increase of the basal NFκB activity in comparison with qHSCs [201, 202]. NFκB promotes antiapoptotic signals in aHSCs predominantly via the classic p65 : p50 complex and low levels of a p65 homodimer [200]. Increased basal activity of NFκB in activated HSCs is linked to downregulation of IκB-α [201]. Interestingly, as a result of liver injury, elevated levels of TNF-α further stimulate NFκB activity. In turn, NFκB mediates antiapoptotic functions and protects aHSCs from TNF-α-induced apoptosis. TNF-α-induced apoptosis of aHSCs can be achieved in the presence of cycloheximide, or pharmacological inhibition of IkB [200].

3.5.5. Stat3 Signaling

Some Jak2-Stat3-signaling cytokines may have a direct effect on aHSCs by facilitating ECM deposition [203, 204]. Leptin increases collagen production in aHSCs/myofibroblasts in fibrotic liver [205207] and promotes HSC survival [205]. Treatment with leptin increases the numbers of HSCs in S and G2/M phases of the cell cycle as well as increases cyclin D1 expression. Leptin mediates its function via activation of the Stat3-Jak2 signaling pathway with downstream activation of ERK, AKT and PI3K [113]. Moreover, other agonists, such as PDGF, EGF and HGF, also activate Stat3 and produce a direct profibrogenic effect on HSCs. As expected, deletion of their corresponding receptors in mice inhibits liver fibrosis [62, 63]. Taken together, there is emerging evidence that supports a significant role of Stat3 in stimulating liver fibrosis. However, the specific role of Stat3 in HSC activation using conditional ablation of Stat3 has not been investigated.

3.6. Portal Fibroblasts (PFs)

Portal fibroblasts are defined as spindle shaped cells of mesenchymal origin that are present in the portal tracts. Under normal conditions, they participate in physiological ECM turnover [208211] and do not express α-SMA. Induced mostly by cholestatic liver injury, portal fibroblasts proliferate, though much slower than HSCs [212], and deposit collagen (e.g., type I) around the portal tracts [213].

The mechanisms of liver fibrogenesis after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment are different. In the CCl4 model, necrosis of hepatocytes and inflammation occurs around centrolobular veins. BDL induces increased biliary pressure and moderate inflammation, causing cytokine secretion by biliary epithelial cells. PFs and HSCs are distributed differently in the hepatic lobule: HSCs resemble pericytes and are located along the sinusoids, in the space of Disse between the endothelium and the hepatocytes, whereas the portal fibroblasts are embedded in the portal tract connective tissue around portal triad [209]. Therefore, the relative activation of HSCs and PFs depend on the model of liver injury [208, 214]. Consistently, PFs have been implicated in pathogenesis of cholestatic liver injury [7, 208]. Unlike toxic liver injury, in cholestatic liver injury, PFs significantly contribute to a population of fibrogenic myofibroblasts compared to HSCs [209]. Peribiliary myofibroblasts express αSMA, collagen Type I, and PDGF receptor-β subunit. In addition, expression of IL-6 is significantly increased in peribiliary myofibroblasts in comparison with activated HSCs [210].

Very little is known about signaling in portal fibroblasts due to the inability to isolate highly purified cells for short term, primary culture. The standard method of isolation of PFs is by outgrowth of peribiliary myofibroblasts from bile duct segments [210, 215]. Differentiating PFs from other fibrogenic myofibroblasts, including aHSCs, is difficult [212]. To date, PFs are distinct from HSCs in that they express elastin (TE-7-positive antigen) and Thy-1.1 (a glycophosphatidylinositol-linked glycoprotein of the outer membrane leaflet described in fibroblasts of several organs) [216218], do not store retinoids, and do not express desmin or neural markers [219]. Several other proteins have been suggested to be upregulated in PFs (versus HSCs), such are fibulin 1 and 2 [220], gremlin [221]. and cofilin 1 [215]. Moreover, PFs do not express cytoglobin, a protein characteristic for aHSCs [215]. In addition, compared to HSCs, PFs express different TGF-β isoforms which may contribute to biliary fibrosis; and distinct from HSCs, PDGF inhibits PFs proliferation and myofibroblastic differentiation [216, 222].

3.6.1. TGF-β-Smad2/3 Signaling

It is anticipated that in response to TGF-β signaling, PFs upregulate collagen Type I and activate the Smad2/3 signaling pathway, similar to HSCs and other myofibroblasts [216]. Our general understanding of TGF-β signaling suggests that mitogenic signaling synergistically promote the growth and invasion of mesenchymal cells [84, 223]. Blocking of phosphorylation of Smad2 abrogates the synergistic responses of fibroblasts to TGF-β and mitogens [9, 84].

4. Closing Remarks

In response to chronic injury, every liver cell contributes to the pathophysiology of liver fibrosis. Several key signaling pathways have emerged that are critical for liver fibrosis. The TGF-β/Smad pathway has been well characterized and demonstrated to affect every liver cell type. More recent studies have demonstrated key roles for other pathways, including TLR4 and Jak/Stat3 in hepatic fibrosis. Furthermore, there is cross-talk between these fibrogenic pathways. For example, activating TLR4 signaling potentiates the TFG-β/Smad pathway. Although the TGF-β pathway might be too important in physiological homeostasis to block as a therapeutic intervention, targeting new cross-talking pathways may provide novel approaches to the treatment of liver fibrosis.

Authors' Contribution

M. Cong, K. Iwaisako, C. Jiang equally contributed to the writing of the paper, designed and provided critical revision of the paper, T. Kisseleva designed and wrote the paper.

Conflict of Interests

The authors declare no conflict of interests.


The paper received funding supported by the National Institutes of Health (GM41804, AA15055, DK72237, and AI077780) and the American Liver Foundation (2006 Liver Scholar Research Award). It is also supported by Grants from David Brenner (NIH RO1 DK090962-01, NIH RO1 DK072237-06, NIH RO1 GM041804-24, and NIH P50 AA011999-13).

HSCs: Hepatic stellate cells
qHSCs: Quiescent HSCs
aHSCs: Activated HSCs
CCl: Carbon tetrachloride
BDL: Bile duct ligation
α-SMA: α-smooth muscle actin
ECM: Extracellular matrix
SMA: α-smooth muscle protein
TGF-β1: Transforming growth factor-β1
LPS: Lipopolysaccharide
LSECs: Liver sinusoidal endothelial cells.

1. Bataller R,Brenner DA. Liver fibrosisJournal of Clinical InvestigationYear: 200511522092182-s2.0-1494438560715690074
2. Kisseleva T,Brenner DA. Fibrogenesis of parenchymal organsProceedings of the American Thoracic SocietyYear: 2008533383422-s2.0-4204909278918403330
3. Seki E,De Minicis S,Österreicher CH,et al. TLR4 enhances TGF-β signaling and hepatic fibrosisNature MedicineYear: 20071311132413322-s2.0-35948958955
4. De Minicis S,Seki E,Uchinami H,et al. Gene expression profiles during hepatic stellate cell activation in culture and in vivoGastroenterologyYear: 20071325193719462-s2.0-3424761936417484886
5. Friedman SL,Roll FJ,Boyles J,Bissell DM. Hepatic lipocytes: the principal collagen-producing cells of normal rat liverProceedings of the National Academy of Sciences of the United States of AmericaYear: 19858224868186852-s2.0-00015200083909149
6. Wells RG. The role of matrix stiffness in regulating cell behaviorHepatologyYear: 2008474139414002-s2.0-4224909329718307210
7. Desmoulière A,Darby I,Costa AMA,et al. Extracellular matrix deposition, lysyl oxidase expression, and myofibroblastic differentiation during the initial stages of cholestatic fibrosis in the ratLaboratory InvestigationYear: 19977667657782-s2.0-00309474469194853
8. Desmoulière A. Hepatic stellate cells: the only cells involved in liver fibrogenesis? A dogma challengedGastroenterologyYear: 20071325205920622-s2.0-3424761549517484899
9. Matsuzaki K. Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cellsCell and Tissue ResearchYear: 20111192-s2.0-79957497507
10. Kisseleva T,Brenner DA. Mechanisms of fibrogenesisExperimental Biology and MedicineYear: 200823321091222-s2.0-3894912802118222966
11. Roberts AB,Heine UI,Flanders KC,Sporn MB. Transforming growth factor-β. Major role in regulation of extracellular matrixAnnals of the New York Academy of SciencesYear: 19905802252322-s2.0-00253756172186691
12. Roberts AB,Flanders KC,Heine UI,et al. Transforming growth factor-beta: multifunctional regulator of differentiation and developmentPhilosophical transactions of the Royal Society of LondonYear: 199032712391451541969655
13. Guo X,Chen SY. Transforming growth factor-beta and smooth muscle differentiationWorld Journal of Biological ChemistryYear: 2012263415222451850
14. Schuster N,Krieglstein K. Mechanisms of TGF-β-mediated apoptosisCell and Tissue ResearchYear: 200230711142-s2.0-003613694311810309
15. Ghosh AK,Varga J. The transcriptional coactivator and acetyltransferase p300 in fibroblast biology and fibrosisJournal of Cellular PhysiologyYear: 200721336636712-s2.0-3584895117617559085
16. Sheppard D. Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosisProceedings of the American Thoracic SocietyYear: 2006354134172-s2.0-3374580876516799084
17. White ES,Baralle FE,Muro AF. New insights into form and function of fibronectin splice variantsJournal of PathologyYear: 200821611142-s2.0-5024917602818680111
18. Yang Z,Mu Z,Dabovic B,et al. Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null miceJournal of Cell BiologyYear: 200717667877932-s2.0-3394726516917353357
19. Murphy-Ullrich JE,Poczatek M. Activation of latent TGF-β by thrombospondin-1: mechanisms and physiologyCytokine and Growth Factor ReviewsYear: 2000111-259692-s2.0-003410921510708953
20. Munger JS,Huang X,Kawakatsu H,et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosisCellYear: 19999633193282-s2.0-003352494910025398
21. Breitkopf K,Haas S,Wiercinska E,Singer MV,Dooley S. Anti-TGF-β strategies for the treatment of chronic liver diseaseAlcoholismYear: 200529supplement 11121S131S2-s2.0-3204443796616344596
22. Breitkopf K,Godoy P,Ciuclan L,Singer MV,Dooley S. TGF-β/Smad signaling in the injured liverZeitschrift fur GastroenterologieYear: 200644157662-s2.0-3194443374116397841
23. Thomas GJ,Nyström ML,Marshall JF. αvβ6 integrin in wound healing and cancer of the oral cavityJournal of Oral Pathology and MedicineYear: 20063511102-s2.0-3364529933116393247
24. Ueberham E,Löw R,Ueberham U,Schönig K,Bujard H,Gebhardt R. Conditional tetracycline-regulated expression of TGF-β1 in liver of transgenic mice leads to reversible intermediary fibrosisHepatologyYear: 2003375106710782-s2.0-003837486612717387
25. Latella G,Vetuschi A,Sferra R,et al. Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in miceLiver InternationalYear: 200929799710092-s2.0-6765050116619422482
26. Leask A,Abraham DJ. TGF-β signaling and the fibrotic responseFASEB JournalYear: 20041878168272-s2.0-214264642615117886
27. Chua F,Dunsmore SE,Clingen PH,et al. Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosisAmerican Journal of PathologyYear: 2007170165742-s2.0-3384705134417200183
28. Shi Y,Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleusCellYear: 200311366857002-s2.0-003868200212809600
29. Arciniegas E,Frid MG,Douglas IS,Stenmark KR. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertensionAmerican Journal of Physiology-Lung Cellular and Molecular PhysiologyYear: 20072931L1L82-s2.0-3444750498717384082
30. Wrana JL. Regulation of Smad activityCellYear: 200010021891922-s2.0-003469551110660041
31. Yoshida K,Matsuzaki K. Differential regulation of TGF-beta/Smad signaling in hepatic stellate cells between acute and chronic liver injuriesFrontiers in PhysiologyYear: 20123p. 53
32. Onichtchouk D,Chen YG,Dosch R,et al. Silencing of TGF-β signalling by the pseudoreceptor BAMBINatureYear: 199940167524804852-s2.0-003361925510519551
33. Border WA,Noble NA,Yamamoto T,et al. Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney diseaseNatureYear: 199236064023613642-s2.0-00266768591280332
34. Oertelt S,Lian ZX,Cheng CM,et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-βreceptor II dominant-negative miceJournal of ImmunologyYear: 20061773165516602-s2.0-33746210257
35. Sato M,Muragaki Y,Saika S,Roberts AB,Ooshima A. Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstructionJournal of Clinical InvestigationYear: 200311210148614942-s2.0-034672732414617750
36. Dooley S,Delvoux B,Streckert M,et al. Transforming growth factor β signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts: TGFβ signal transduction during transdifferentiation of hepatic stellate cellsFEBS LettersYear: 20015021-24102-s2.0-003595862511478938
37. Hayashida T. Integrins modulate cellular fibrogenesis at multiple levels; Regulation of TGF-β signaling.Endocrine, metabolic & immune disorders drug targetsYear: 20101043023192-s2.0-79954500351
38. Derynck R,Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signallingNatureYear: 200342569585775842-s2.0-014210498514534577
39. Shih VFS,Tsui R,Caldwell A,Hoffmann A. A single NFκB system for both canonical and non-canonical signalingCell ResearchYear: 2011211861022-s2.0-7865090744521102550
40. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insightsAnnual Review of ImmunologyYear: 199614649683
41. Ghosh S,May MJ,Kopp EB. NF-κB and rel proteins: evolutionarily conserved mediators of immune responsesAnnual Review of ImmunologyYear: 1998162252602-s2.0-0031897632
42. Karin M,Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activityAnnual Review of ImmunologyYear: 2000186216632-s2.0-0034084163
43. Scheidereit C. IκB kinase complexes: gateways to NF-κB activation and transcriptionOncogeneYear: 20062551668567052-s2.0-3375044328917072322
44. Rudolph D,Yeh WC,Wakeham A,et al. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient miceGenes & DevelopmentYear: 200014785486210766741
45. Li Q,Van Antwerp D,Mercurio F,Lee KF,Verma IM. Severe liver degeneration in mice lacking the IκB kinase 2 geneScienceYear: 199928454123213252-s2.0-003353773910195897
46. Beg AA,Sha WC,Bronson RT,Ghosh S,Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κBNatureYear: 199537665361671702-s2.0-00290590607603567
47. Luedde T,Heinrichsdorff J,De Lorenzi R,De Vos R,Roskams T,Pasparakis M. IKK1 and IKK2 cooperate to maintain bile duct integrity in the liverProceedings of the National Academy of Sciences of the United States of AmericaYear: 200810528973397382-s2.0-4774913626718606991
48. Yin L,Wu L,Wesche H,et al. Defective lymphotoxin-β receptor-induced NF-κB transcriptional activity in NIK-deficient miceScienceYear: 20012915511216221652-s2.0-003589642211251123
49. Yilmaz ZB,Weih DS,Sivakumar V,Weih F. RelB is required for Peyer’s patch development: differential regulation of p52-RelB by lymphotoxin and TNFEMBO JournalYear: 20032211211302-s2.0-003741370912505990
50. Yang D,Oppenheim JJ. Antimicrobial proteins act as “Alarmins” in joint immune defenseArthritis and RheumatismYear: 20045011340134032-s2.0-844422935315529365
51. Aoyama T,Paik YH,Seki E. Toll-like receptor signaling and liver fibrosisGastroenterology Research and PracticeYear: 201020108 pages2-s2.0-77956810224192543
52. Pamer EG. TLR polymorphisms and the risk of invasive fungal infectionsNew England Journal of MedicineYear: 200835917183618382-s2.0-5494915371918946070
53. Yan AW,Schnabl B. Bacterial translocation and changes in the intestinal microbiome associated with alcoholic liver diseaseWorld Journal of HepatologyYear: 20124411011822567183
54. Iwaisako K,Haimerl M,Paik YH,et al. et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonistProceedings of the National Academy of Sciences of the United States of AmericaYear: 20121092113691376
55. Fouts DE,Torralba M,Nelson KE,Brenner DA,Schnabl B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver diseaseJournal of HepatologyYear: 20125661283129222326468
56. Seki E,Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gutJournal of PhysiologyYear: 2012590344745822124143
57. Albillos A,la Hera AD,González M,et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangementHepatologyYear: 20033712082172-s2.0-003721939312500206
58. Isayama F,Hines IN,Kremer M,et al. LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in miceAmerican Journal of Physiology-Gastrointestinal and Liver PhysiologyYear: 20062906G1318G13282-s2.0-3364686238316439470
59. White ES,Muro AF. Fibronectin splice variants: understanding their multiple roles in health and disease using engineered mouse modelsIUBMB LifeYear: 20116375385462-s2.0-7995959640621698758
60. Okamura Y,Watari M,Jerud ES,et al. The extra domain A of fibronectin activates toll-like receptor 4Journal of Biological ChemistryYear: 20012761310229102332-s2.0-003597121711150311
61. Xu XH,Shah PK,Faure E,et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDLCirculationYear: 200110425310331082-s2.0-003591001011748108
62. Kisseleva T,Bhattacharya S,Braunstein J,Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challengesGeneYear: 20022851-21242-s2.0-003713837012039028
63. Gao B. Cytokines, STATs and liver diseaseCellular & Molecular ImmunologyYear: 200522921002-s2.0-3294446350716191414
64. Akira S,Nishio Y,Inoue M,et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathwayCellYear: 199477163712-s2.0-00283039777512451
65. Bowman T,Garcia R,Turkson J,Jove R. STATs in oncogenesisOncogeneYear: 20001921247424882-s2.0-003465869810851046
66. Takeda K,Noguchi K,Shi W,et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethalityProceedings of the National Academy of Sciences of the United States of AmericaYear: 1997948380138042-s2.0-00309352609108058
67. Takeda K,Kaisho T,Yoshida N,Takeda J,Kishimoto T,Akira S. Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell- specific stat3-deficient miceJournal of ImmunologyYear: 19981619465246602-s2.0-0032213273
68. Takeda K,Clausen BE,Kaisho T,et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of stat3 in macrophages and neutrophilsImmunityYear: 199910139492-s2.0-003303436510023769
69. Chapman RS,Lourenco PC,Tonner E,et al. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3Genes and DevelopmentYear: 19991319260426162-s2.0-003321490310521404
70. Alonzi T,Maritano D,Gorgoni B,Rizzuto G,Libert C,Poli V. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene activation in the liverMolecular and Cellular BiologyYear: 2001215162116322-s2.0-003513119011238899
71. Plum W,Tschaharganeh DF,Kroy DC,et al. Lack of glycoprotein 130/signal transducer and activator of transcription 3-mediated signaling in hepatocytes enhances chronic liver injury and fibrosis progression in a model of sclerosing cholangitisAmerican Journal of PathologyYear: 20101765223622462-s2.0-7795207541420382701
72. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigmNature Reviews ImmunologyYear: 200448583594
73. Kovalovich K,Deangelis RA,Li W,Furth EE,Ciliberto G,Taub R. Increased toxin-induced liver injury and fibrosis in interleukin-6- deficient miceHepatologyYear: 20003111491592-s2.0-003397096910613740
74. Louis H,Le Moine O,Goldman M,Devière J. Modulation of liver injury by interleukin-10Acta Gastro-Enterologica BelgicaYear: 20036617142-s2.0-003722299712812143
75. Streetz KL,Wüstefeld T,Klein C,et al. Lack of gp130 expression in hepatocytes promotes liver injuryGastroenterologyYear: 200312525325432-s2.0-004316791012891556
76. Ki SH,Park O,Zheng M,et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3.HepatologyYear: 2010524129113002-s2.0-7795794641520842630
77. Zenewicz LA,Yancopoulos GD,Valenzuela DM,Murphy AJ,Karow M,Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammationImmunityYear: 20072746476592-s2.0-3534898334117919941
78. Wang H,Lafdil F,Kong X,Gao B. Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic targetInternational Journal of Biological SciencesYear: 2011755365502-s2.0-7995575657521552420
79. Kuo TK,Hung SP,Chuang CH,et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cellsGastroenterologyYear: 200813472111e32-s2.0-4464913684518455168
80. Cressman DE,Greenbaum LE,DeAngelis RA,et al. Liver failure and defective hepatocyte regeneration in interleukin-6- deficient miceScienceYear: 19962745291137913832-s2.0-00298467568910279
81. Hata S,Namae M,Nishina H. Liver development and regeneration: from laboratory study to clinical therapyDevelopment Growth and DifferentiationYear: 20074921631702-s2.0-33847194249
82. Michalopoulos GK,DeFrances MC. Liver regenerationScienceYear: 1997276530960652-s2.0-00308944499082986
83. Kawamata S,Matsuzaki K,Murata M,et al. Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesisInflammatory Bowel DiseasesYear: 20111736836952-s2.0-7995162644320602465
84. Matsuzaki K,Kitano C,Murata M,et al. Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-β signal in later stages of human colorectal cancerCancer ResearchYear: 20096913532153302-s2.0-6765046636819531654
85. Harper JW,Adami GR,Wei N,Keyomarsi K,Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin- dependent kinasesCellYear: 19937548058162-s2.0-00274969358242751
86. Date M,Matsuzaki K,Matsushita M,et al. Diffrential expression of transforming growth factor-β and its receptors in hepatocytes and nonparenchymal cells of rat liver after CCl4 administrationJournal of HepatologyYear: 19982845725812-s2.0-00315967199566825
87. Date M,Matsuzaki K,Matsushita M,Tahashi Y,Sakitani K,Inoue K. Differential regulation of activin A for hepatocyte growth and fibronectin synthesis in rat liver injuryJournal of HepatologyYear: 20003222512602-s2.0-003396771310707865
88. Matsuzaki K,Murata M,Yoshida K,et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinomaHepatologyYear: 200746148572-s2.0-3434723220517596875
89. Nagata H,Hatano E,Tada M,et al. Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor-suppression in rat hepatocellular carcinomaHepatologyYear: 2009496194419532-s2.0-6765037732919418558
90. Zavadil J,Bitzer M,Liang D,et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-βProceedings of the National Academy of Sciences of the United States of AmericaYear: 20019812668666912-s2.0-003581094411390996
91. Zeisberg M,Neilson EG. Biomarkers for epithelial-mesenchymal transitionsJournal of Clinical InvestigationYear: 20091196142914372-s2.0-6765099675419487819
92. Iwano M,Plieth D,Danoff TM,Xue C,Okada H,Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosisJournal of Clinical InvestigationYear: 200211033413502-s2.0-003632200712163453
93. Kalluri R,Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosisJournal of Clinical InvestigationYear: 200311212177617842-s2.0-034672451114679171
94. Neilson EG. Mechanisms of disease: fibroblasts—a new look at an old problemNature Clinical Practice NephrologyYear: 200622101108
95. Zeisberg M,Yang C,Martino M,et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transitionJournal of Biological ChemistryYear: 20072823223337233472-s2.0-3454814581517562716
96. Kisseleva T,Brenner DA. Is it the end of the line for the EMT?HepatologyYear: 2011535143314352-s2.0-7995512014521433040
97. Taura K,Miura K,Iwaisako K,et al. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in miceHepatologyYear: 2010513102710362-s2.0-7795059770720052656
98. Gebhardt C,Németh J,Angel P,Hess J. S100A8 and S100A9 in inflammation and cancerBiochemical PharmacologyYear: 20067211162216312-s2.0-3375050588316846592
99. Nacken W,Roth J,Sorg C,Kerkhoff C. S100A9/S100A8: myeloid representatives of the S100 protein family as prominent players in innate immunityMicroscopy research and techniqueYear: 20036065695802-s2.0-024233560012645005
100. Osterreicher CH,Penz-Osterreicher M,Grivennikov SI,et al. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liverProceedings of the National Academy of Sciences of the United States of AmericaYear: 2011108130831321173249
101. Kinoshita K,Iimuro Y,Otogawa K,et al. Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in ratsGutYear: 20075657067142-s2.0-3424749673517127702
102. Weiskirchen R,Meurer SK,Gressner OA,Herrmann J,Borkham-Kamphorst E,Gressner AM. BMP-7 as antagonist of organ fibrosisFrontiers in BioscienceYear: 20091413499250122-s2.0-6914910908819482601
103. Jones CN,Tuleuova N,Lee JY,et al. Cultivating hepatocytes on printed arrays of HGF and BMP7 to characterize protective effects of these growth factors during in vitro alcohol injuryBiomaterialsYear: 20103123593659442-s2.0-7795381125820488537
104. Zhu L,Wang L,Wang X,et al. Hepatic deletion of Smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injuryPLoS ONEYear: 2011622-s2.0-79952254584e17415
105. Crispe IN. The liver as a lymphoid organAnnual Review of ImmunologyYear: 200927147163
106. Seki E,Brenner DA. Toll-like receptors and adaptor molecules in liver disease: updateHepatologyYear: 20084813223352-s2.0-4714910503618506843
107. Liu S,Gallo DJ,Green AM,et al. Role of toll-like receptors in changes in gene expression and NF-κB activation in mouse hepatocytes stimulated with lipopolysaccharideInfection and ImmunityYear: 2002707343334422-s2.0-003608472812065483
108. Chen Y,Sun R. Toll-like receptors in acute liver injury and regenerationInternational ImmunopharmacologyYear: 20111110143314412-s2.0-7995746110321601014
109. Matsumura T,Ito A,Takii T,Hayashi H,Onozaki K. Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytesJournal of Interferon and Cytokine ResearchYear: 200020109159212-s2.0-003377991511054280
110. Campbell JS,Riehle KJ,Brooling JT,Bauer RL,Mitchell C,Fausto N. Proinflammatory cytokine production in liver regeneration is Myd88-dependent, but independent of Cd14, Tlr2, and Tlr4Journal of ImmunologyYear: 20061764252225282-s2.0-32044455139
111. Burstein E,Duckett CS. Dying for NF-κB? Control of cell death by transcriptional regulation of the apoptotic machineryCurrent Opinion in Cell BiologyYear: 20031567327372-s2.0-034484500214644198
112. Lehmann V,Freudenberg MA,Galanos C. Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated miceJournal of Experimental MedicineYear: 198716536576632-s2.0-00231754683819645
113. Elsharkawy AM,Oakley F,Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosisApoptosisYear: 20051059279392-s2.0-2464448875116151628
114. Akira S. Roles of STAT3 defined by tissue-specific gene targetingOncogeneYear: 20001921260726112-s2.0-003465795810851059
115. Waelput W,Verhee A,Broekaert D,et al. Identification and expression analysis of leptin-regulated immediate early response and late target genesBiochemical JournalYear: 2000348155612-s2.0-003465723110794713
116. Terui K,Ozaki M. The role of STAT3 in liver regenerationDrugs of TodayYear: 20054174614692-s2.0-2684450837116193099
117. Li W,Liang X,Kellendonk C,Poli V,Taub R. STAT3 contributes to the mitogenic response of hepatocytes during liver regenerationJournal of Biological ChemistryYear: 20022773228411284172-s2.0-003704736012032149
118. Fujiyoshi M,Ozaki M. Molecular mechanisms of liver regeneration and protection for treatment of liver dysfunction and diseasesJournal of Hepato-Biliary-Pancreatic SciencesYear: 201118113222-s2.0-7995779125820607568
119. Kovalovich K,Li W,DeAngelis R,Greenbaum LE,Ciliberto G,Taub R. Interleukin-6 protects against fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xLJournal of Biological ChemistryYear: 20012762826605266132-s2.0-003585478011349125
120. Mair M,Zollner G,Schneller D,et al. Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitisGastroenterologyYear: 20101387249925082-s2.0-7795269983620193684
121. Haga S,Terui K,Zhang HQ,et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanismsJournal of Clinical InvestigationYear: 200311279899982-s2.0-024234879314523036
122. Terui K,Enosawa S,Haga S,et al. Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes through upregulation of Mn-SODJournal of HepatologyYear: 20044169579652-s2.0-2084444177015582129
123. Zi Y,Wang Y,Wiegmann PS,et al. In vivo treatment of HCV core-positive HepG2 cells with the transfer of recombinant caspase-3 using a 2’-5’ OAS promoterMolecular Medicine ReportsYear: 20125363163622159511
124. Aoyama T,Inokuchi S,Brenner DA,Seki E. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice.Hepatology (Baltimore, Md.)Year: 2010524139014002-s2.0-77957956790
125. Seki E,De Minicis S,Inokuchi S,et al. CCR2 promotes hepatic fibrosis in miceHepatologyYear: 20095011851972-s2.0-6765115635319441102
126. Seki E,Tsutsui H,Nakano H,et al. Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1βJournal of ImmunologyYear: 20011664265126572-s2.0-0035865249
127. Gao B,Seki E,Brenner DA,et al. Innate immunity in alcoholic liver diseaseAmerican Journal of Physiology-Gastrointestinal and Liver PhysiologyYear: 20113004G516G5252-s2.0-7995506277321252049
128. Yasukawa H,Ohishi M,Mori H,et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophagesNature ImmunologyYear: 2003465515562-s2.0-003760074112754507
129. Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertensionLiver InternationalYear: 20113221992132-s2.0-7995985095021745318
130. Thabut D,Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension?Journal of HepatologyYear: 20105359769802-s2.0-7795732851820800926
131. Jagavelu K,Routray C,Shergill U,O’Hara SP,Faubion W,Shah VH. Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liverHepatologyYear: 20105225906012-s2.0-7795568623320564354
132. Iwakiri Y,Groszmann RJ. Vascular endothelial dysfunction in cirrhosisJournal of HepatologyYear: 20074659279342-s2.0-3404717587617391799
133. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseasesJournal of Clinical InvestigationYear: 200711735245292-s2.0-3384735069117332879
134. Otrock ZK,Mahfouz RAR,Makarem JA,Shamseddine AI. Understanding the biology of angiogenesis: review of the most important molecular mechanismsBlood Cells, Molecules, and DiseasesYear: 20073922122202-s2.0-34547221505
135. Kang DH,Johnson RJ. Vascular endothelial growth factor: a new player in the pathogenesis of renal fibrosisCurrent Opinion in Nephrology and HypertensionYear: 200312143492-s2.0-003722749612496665
136. Ushio-Fukai M. VEGF signaling through NADPH oxidase-derived ROSAntioxidants and Redox SignalingYear: 2007967317392-s2.0-3424907132617511588
137. Taura K,De Minicis S,Seki E,et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosisGastroenterologyYear: 20081355172917382-s2.0-5524912566918823985
138. Makinde T,Murphy RF,Agrawal DK. Immunomodulatory role of vascular endothelial growth factor and angiopoietin-1 in airway remodelingCurrent Molecular MedicineYear: 2006688318412-s2.0-3384535084917168735
139. Fernandez M,Mejias M,Angermayr B,Garcia-Pagan JC,Rodés J,Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive ratsJournal of HepatologyYear: 2005431981032-s2.0-2044436798415893841
140. Abraldes JG,Iwakiri Y,Loureiro-Silva M,Haq O,Sessa WC,Groszmann RJ. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic stateAmerican Journal of Physiology-Gastrointestinal and Liver PhysiologyYear: 20062905G980G9872-s2.0-3364579996516603731
141. Greenberg JI,Shields DJ,Barillas SG,et al. A role for VEGF as a negative regulator of pericyte function and vessel maturationNatureYear: 2009456809p. 8132-s2.0-61349191503
142. Wynn TA. Cellular and molecular mechanisms of fibrosisJournal of PathologyYear: 200821421992102-s2.0-3854915902618161745
143. Goumans MJ,Mummery C. Functional analysis of the TGFβ receptor/Smad pathway through gene ablation in miceInternational Journal of Developmental BiologyYear: 20004432532652-s2.0-003362541610853822
144. Goumans MJ,Liu Z,Ten Dijke P. TGF-β signaling in vascular biology and dysfunctionCell ResearchYear: 20091911161272-s2.0-5814923097919114994
145. Orlova VV,Liu Z,Goumans MJ,et al. Controlling angiogenesis by two unique TGF-beta type I receptor signaling pathwaysHistology and HistopathologyYear: 20112691219123021751154
146. Pepper MS. Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrityCytokine and Growth Factor ReviewsYear: 19978121432-s2.0-00311064049174661
147. Lai YT,Beason KB,Brames GP,et al. Activin receptor-like kinase 2 can mediate atrioventricular cushion transformationDevelopmental BiologyYear: 200022211112-s2.0-003421360910885742
148. Arthur HM,Ure J,Smith AJH,et al. Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart developmentDevelopmental BiologyYear: 2000217142532-s2.0-003362180410625534
149. Lebrin F,Goumans MJ,Jonker L,et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transductionEMBO JournalYear: 20042320401840282-s2.0-814423070715385967
150. Rudini N,Felici A,Giampietro C,et al. VE-cadherin is a critical endothelial regulator of TGF-β signallingEMBO JournalYear: 200827799310042-s2.0-4194911217318337748
151. Zeisberg EM,Tarnavski O,Zeisberg M,et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosisNature MedicineYear: 20071389529612-s2.0-34547676391
152. Zeisberg EM,Potenta SE,Sugimoto H,Zeisberg M,Kalluri R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transitionJournal of the American Society of NephrologyYear: 20081912228222872-s2.0-5524910343118987304
153. Goumans MJ,van Zonneveld AJ,ten Dijke P. Transforming growth factor β-induced endothelial-to-mesenchymal transition: a switch to cardiac fibrosis?Trends in Cardiovascular MedicineYear: 20081882932982-s2.0-6344911027419345316
154. Kisseleva T,Brenner DA. Hepatic stellate cells and the reversal of fibrosisJournal of Gastroenterology and HepatologyYear: 200621supplement 3S84S872-s2.0-3374758486716958681
155. Tiegs G,Lohse AW. Immune tolerance: what is unique about the liverJournal of AutoimmunityYear: 2010341162-s2.0-7514919666619717280
156. Magder S,Neculcea J,Neculcea V,Sladek R. Lipopolysaccharide and TNF-α produce very similar changes in gene expression in human endothelial cellsJournal of Vascular ResearchYear: 20064354474612-s2.0-3374875316116921252
157. Kisseleva T,Song L,Vorontchikhina M,Feirt N,Kitajewski J,Schindler C. NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancerJournal of Clinical InvestigationYear: 200611611295529632-s2.0-3375057699617053836
158. Sun Z,Klein AS,Radaeva S,et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in ratsGastroenterologyYear: 200312512022152-s2.0-003857546712851884
159. Gao B. Therapeutic potential of interleukin-6 in preventing obesity- and alcohol-associated fatty liver transplant failureAlcoholYear: 200434159652-s2.0-1274427608015670667
160. Miller AM,Horiguchi N,Jeong WI,Radaeva S,Gao B. Molecular mechanisms of alcoholic liver disease: innate immunity and cytokinesAlcoholismYear: 20113557877932-s2.0-7995546278821284667
161. Miller AM,Wang H,Park O,et al. Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injuryAlcoholismYear: 20103447197252-s2.0-7794997584020102572
162. Larusso NF,Masyuk TV. The role of cilia in the regulation of bile flowDigestive DiseasesYear: 20112916122-s2.0-7995949182421691098
163. Means AL,Xu Y,Zhao A,Ray KC,Gu G. A CK19CreERT knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organsGenesisYear: 20084663183232-s2.0-4754911912718543299
164. Kisseleva T,Gigante E,Brenner DA. Recent advances in liver stem cell therapyCurrent Opinion in GastroenterologyYear: 20102643954022-s2.0-7795414386520495456
165. Harada K,Shimoda S,Sato Y,Isse K,Ikeda H,Nakanuma Y. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosisClinical and Experimental ImmunologyYear: 200915722612702-s2.0-6765066874119604266
166. Penz-Osterreicher M,Osterreicher CH,Trauner M. Fibrosis in autoimmune and cholestatic liver diseaseBest Practice and ResearchYear: 2011252245258
167. Omenetti A,Yang L,Li YX,et al. Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligationLaboratory InvestigationYear: 20078754995142-s2.0-3424736979717334411
168. Omenetti A,Porrello A,Jung Y,et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humansJournal of Clinical InvestigationYear: 200811810333133422-s2.0-5584913560018802480
169. Scholten D,Österreicher CH,Scholten A,et al. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in miceGastroenterologyYear: 201013939879982-s2.0-7795615810320546735
170. Chu AS,Diaz R,Hui JJ,et al. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosisHepatologyYear: 2011535168516952-s2.0-7995512395121520179
171. Chen XM,Splinter PL,O’Hara SP,LaRusso NF. A cellular micro-RNA, let-7i, regulates toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infectionJournal of Biological ChemistryYear: 20072823928929289382-s2.0-3534892940217660297
172. O’Hara SP,Splinter PL,Trussoni CE,Gajdos GB,Lineswala PN,LaRusso NF. Cholangiocyte N-Ras protein mediates lipopolysaccharide-induced interleukin 6 secretion and proliferationJournal of Biological ChemistryYear: 201128635303523036021757746
173. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organJournal of Clinical InvestigationYear: 200711735395482-s2.0-3384736320317332881
174. Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cellsSeminars in Liver DiseaseYear: 20012133113352-s2.0-003480831011586463
175. Sachs BD,Baillie GS,McCall JR,et al. p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathwayJournal of Cell BiologyYear: 20071776111911322-s2.0-3425073232417576803
176. Kendall TJ,Hennedige S,Aucott RL,et al. P75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosisHepatologyYear: 20094939019102-s2.0-6334910644219072833
177. Senoo H,Kojima N,Sato M. Vitamin A-storing cells (Stellate Cells)Vitamins and HormonesYear: 2007751311592-s2.0-3394724897217368315
178. Bataller R,Schwabe RF,Choi YH,et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosisJournal of Clinical InvestigationYear: 20031129138313942-s2.0-034798677714597764
179. Winau F,Hegasy G,Weiskirchen R,et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responsesImmunityYear: 20072611171292-s2.0-3384621234717239632
180. Asahina K,Tsai SY,Li P,et al. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver developmentHepatologyYear: 200949399810112-s2.0-6334910930919085956
181. Sanderson N,Factor V,Nagy P,et al. Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesionsProceedings of the National Academy of Sciences of the United States of AmericaYear: 1995927257225762-s2.0-00289537687708687
182. Schnabl B,Kweon YO,Frederick JP,Wang XF,Rippe RA,Brenner DA. The role of Smad3 in mediating mouse hepatic stellate cell activationHepatologyYear: 2001341891002-s2.0-003495655911431738
183. Dooley S,Hamzavi J,Breitkopf K,et al. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in ratsGastroenterologyYear: 200312511781912-s2.0-003771640612851882
184. Hamzavi J,Ehnert S,Godoy P,et al. Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in miceJournal of Cellular and Molecular MedicineYear: 2008125B213021442-s2.0-5434908469918266971
185. Wiercinska E,Wickert L,Denecke B,et al. Id1 Is a critical mediator in TGF-β-induced transdifferentiation of rat hepatic stellate cellsHepatologyYear: 2006435103210412-s2.0-3364669172016628634
186. Fibbi G,Pucci M,D’Alessio S,et al. Transforming growth factor beta-1 stimulates invasivity of hepatic stellate cells by engagement of the cell-associated fibrinolytic systemGrowth FactorsYear: 2001192871002-s2.0-003521409711769974
187. Yang C,Zeisberg M,Mosterman B,et al. Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factorsGastroenterologyYear: 200312411471592-s2.0-003722191012512039
188. Maehama T,Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphateJournal of Biological ChemistryYear: 19982732213375133782-s2.0-00325776999593664
189. Reif S,Lang A,Lindquist JN,et al. The role of focal adhesion kinase-phosphatidylinositol 3-kinase-Akt signaling in hepatic stellate cell proliferation and type I collagen expressionJournal of Biological ChemistryYear: 200327810808380902-s2.0-003742449812502711
190. Takashima M,Parsons CJ,Ikejima K,Watanabe S,White ES,Rippe RA. The tumor suppressor protein PTEN inhibits rat hepatic stellate cell activationJournal of GastroenterologyYear: 20094488478552-s2.0-6934908688119436944
191. Pinzani M,Marra F. Cytokine receptors and signaling in hepatic stellate cellsSeminars in Liver DiseaseYear: 20012133974162-s2.0-003481008911586468
192. Marra F,Arrighi MC,Fazi M,et al. Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor’s actions in hepatic stellate cells, and is induced by in vivo liver injury in the ratHepatologyYear: 19993049519582-s2.0-003286256010498647
193. Li J,Yen C,Liaw D,et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancerScienceYear: 19972755308194319472-s2.0-00309363239072974
194. Kwak YG,Song CH,Yi HK,et al. Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthmaJournal of Clinical InvestigationYear: 20031117108310922-s2.0-003738280812671058
195. White ES,Thannickal VJ,Carskadon SL,et al. Integrin α4β1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10American Journal of Respiratory and Critical Care MedicineYear: 200316844364422-s2.0-004182715512791582
196. Pap T,Franz JK,Hummel KM,Jeisy E,Gay R,Gay S. Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumour suppressor PTEN at sites of invasive growth and destructionArthritis ResearchYear: 20002159642-s2.0-003446705811219390
197. Cui W,Matsuno K,Iwata K,et al. NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligationHepatologyYear: 2011549499582-s2.0-7996068147021618578
198. Heldin CH,Westermark B. Mechanism of action and in vivo role of platelet-derived growth factorPhysiological ReviewsYear: 1999794128313162-s2.0-003287546010508235
199. Pinzani M,MacIas-Barragan J. Update on the pathophysiology of liver fibrosisExpert Review of Gastroenterology and HepatologyYear: 2010444594722-s2.0-7795524900520678019
200. Mann DA,Smart DE. Transcriptional regulation of hepatic stellate cell activationGutYear: 20025068918962-s2.0-003610754812010897
201. Elsharkawy AM,Wright MC,Hay RT,et al. Persistent activation of nuclear factor-κB in cultured rat hepatic stellate cells involves the induction of potentially novel rel-like factors and prolonged changes in the expression of IκB family proteinsHepatologyYear: 19993037617692-s2.0-003284185610462383
202. Mann J,Mann DA. Transcriptional regulation of hepatic stellate cellsAdvanced Drug Delivery ReviewsYear: 2009617-84975122-s2.0-6574910380819393271
203. Hosui A,Kimura A,Yamaji D,Zhu BM,Na R,Hennighausen L. Loss of STAT5 causes Liver fbrosis and cancer development through increased TGF-β and STAT3 activationJournal of Experimental MedicineYear: 200920648198312-s2.0-6554909459519332876
204. Ogata H,Chinen T,Yoshida T,et al. Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 productionOncogeneYear: 20062517252025302-s2.0-3364614673416474852
205. Saxena NK,Titus MA,Ding X,et al. Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylationFASEB JournalYear: 20041813161216142-s2.0-944422384515319373
206. Choi SS,Syn WK,Karaca GF,et al. Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the Hedgehog pathwayJournal of Biological ChemistryYear: 20102854736551365602-s2.0-7844924095120843817
207. Liu Y,Brymora J,Zhang H,et al. Leptin and acetaldehyde synergistically promotes αSMA expression in hepatic stellate cells by an interleukin6-dependent mechanismAlcoholismYear: 20113559219282-s2.0-7995548460421294755
208. Tuchweber B,Desmoulière A,Bochaton-Piallat ML,Rubbia-Brandt L,Gabbiani G. Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the ratLaboratory InvestigationYear: 19967412652782-s2.0-00300329058569191
209. Guyot C,Lepreux S,Combe C,et al. Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involvedInternational Journal of Biochemistry and Cell BiologyYear: 20063821351512-s2.0-2774458066916257564
210. Kinnman N,Francoz C,Barbu V,et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesisLaboratory InvestigationYear: 20038321631732-s2.0-003732989612594232
211. Parola M,Marra F,Pinzani M. Myofibroblast-like cells and liver fibrogenesis: emerging concepts in a rapidly moving scenarioMolecular Aspects of MedicineYear: 2008291-258662-s2.0-3974917063918022682
212. Wells RG,Kruglov E,Dranoff JA. Autocrine release of TGF-β by portal fibroblasts regulates cell growthFEBS LettersYear: 20045591–31071102-s2.0-044232348814960316
213. Knittel T,Kobold D,Salle B,et al. Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potentialGastroenterologyYear: 19991175120512212-s2.0-003274205110535885
214. Tang L,Tanaka Y,Marumo F,Sato C. Phenotypic change in portal fibrosis in biliary fibrosisLiverYear: 199414276822-s2.0-00282652908196513
215. Bosselut N,Housset C,Marcelo P,et al. Distinct proteomic features of two fibrogenic liver cell populations: hepatic stellate cells and portal myofibroblastsProteomicsYear: 2010105101710282-s2.0-7764916823720049859
216. Dranoff JA,Wells RG. Portal fibroblasts: underappreciated mediators of biliary fibrosisHepatologyYear: 2010514143814442-s2.0-7795061168220209607
217. Dudas J,Mansuroglu T,Batusic D,Saile B,Ramadori G. Thy-1 is an in vivo and in vitro marker of liver myofibroblastsCell and Tissue ResearchYear: 200732935035142-s2.0-3454780811717576600
218. Yovchev MI,Zhang J,Neufeld DS,Grozdanov PN,Dabeva MD. Thymus cell antigen-1-expressing cells in the oval cell compartmentHepatologyYear: 20095026016112-s2.0-6894918934019575449
219. Forbes SJ,Parola M. Liver fibrogenic cellsBest Practice and ResearchYear: 20112522072172-s2.0-79954473094
220. Knittel T,Kobold D,Piscaglia F,et al. Localization of liver myofibroblasts and hepatic stellate cells in normal and diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic tissue repairHistochemistry and Cell BiologyYear: 199911253874012-s2.0-003273747810603079
221. Dudas J,Mansuroglu T,Batusic D,Ramadori G. Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury.Histochemistry and cell biologyYear: 200913111151272-s2.0-6584939063718797914
222. Forbes SJ,Parola M. Liver fibrogenic cellsBest Practice and ResearchYear: 20112522072172-s2.0-79954473094
223. Matsuura I,Chiang KN,Lai CY,et al. Pin1 promotes transforming growth factor-β-induced migration and invasionJournal of Biological ChemistryYear: 20102853175417642-s2.0-7624909003719920136

Article Categories:
  • Review Article

Previous Document:  Obstacles to obtaining optimal physiotherapy services in a rural community in southeastern Nigeria.
Next Document:  Overview of hepatocellular adenoma in Japan.