Document Detail


Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor β.
MedLine Citation:
PMID:  23335246     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To explore the expression of thymic stromal lymphopoietin (TSLP) in patients with diffuse cutaneous systemic sclerosis (dcSSc) and compare its effects in vivo and in vitro with those of interleukin-13 (IL-13) and transforming growth factor β (TGFβ).
METHODS: Skin biopsy specimens from patients with dcSSc (n = 14) and healthy controls (n = 13) were analyzed by immunohistochemistry and immunofluorescence for TSLP, TSLP receptor, CD4, CD8, CD31, and CD163 markers. Wild-type, IL-4Rα1-, and TSLP-deficient mice were treated with TGFβ, IL-13, poly(I-C), or TSLP by osmotic pump. Human fibroblasts and peripheral blood mononuclear cells (PBMCs) were stimulated with TGFβ, IL-13, poly(I-C), or TSLP. Microarray analysis and quantitative polymerase chain reaction were performed to determine gene expression, and protein levels of phospho-Smad2 and macrophage marker CD163 were tested.
RESULTS: TSLP was highly expressed in the skin of dcSSc patients, more strongly in perivascular areas and in immune cells, and was produced mainly by CD163+ cells. The skin of TSLP-treated mice showed up-regulated clusters of gene expression that overlapped strongly with those in IL-13- and TGFβ-treated mice. TSLP up-regulated specific genes, including CXCL9, proteasome, and interferon (IFN)-regulated genes. TSLP treatment in IL-4Rα1-deficient mice promoted similar cutaneous inflammation as in wild-type mice, though TSLP-induced arginase 1, CCL2, and matrix metalloproteinase 12 messenger RNA levels were blocked. In PBMCs, TSLP up-regulated tumor necrosis factor α, Mx-1, IFNγ, CXCL9, and mannose receptor 1 gene expression. TSLP-deficient mice treated with TGFβ showed less fibrosis and blocked expression of plasminogen activator inhibitor 1 and osteopontin 1. Poly(I-C)-treated mice showed high levels of cutaneous TSLP.
CONCLUSION: TSLP is highly expressed in the skin of dcSSc patients and interacts in a complex manner with 2 other profibrotic cytokines, TGFβ and IL-13, strongly suggesting that it might promote SSc fibrosis directly or indirectly by synergistically stimulating profibrotic genes, or production of these cytokines.
Authors:
Romy B Christmann; Allison Mathes; Alsya J Affandi; Cristina Padilla; Banafsheh Nazari; Andreea M Bujor; Giuseppina Stifano; Robert Lafyatis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  65     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-24     Completed Date:  2013-06-18     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1335-46     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 by the American College of Rheumatology.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Markers / metabolism
Cytokines / biosynthesis*,  deficiency,  pharmacology
Fibroblasts / drug effects,  metabolism,  pathology
Fibrosis / genetics*
Gene Expression / drug effects
Humans
Interleukin-13 / metabolism*,  pharmacology
Intracellular Signaling Peptides and Proteins / metabolism*
Leukocytes, Mononuclear / drug effects,  metabolism,  pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Poly I-C / pharmacology
RNA, Messenger / metabolism
Scleroderma, Diffuse / diagnosis,  metabolism*
Skin / metabolism*,  pathology
Transforming Growth Factor beta / metabolism*,  pharmacology
Up-Regulation
Grant Support
ID/Acronym/Agency:
1P50-AR-060780-02/AR/NIAMS NIH HHS; 2R01-AR-051089-06A1/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Cytokines; 0/Interleukin-13; 0/Intracellular Signaling Peptides and Proteins; 0/RNA, Messenger; 0/Transforming Growth Factor beta; 0/thymic stromal lymphopoietin; 24939-03-5/Poly I-C

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