Document Detail

FOXO1 increases CCL20 to promote NF-κB-dependent lymphocyte chemotaxis.
MedLine Citation:
PMID:  22240809     Owner:  NLM     Status:  MEDLINE    
Hepatic insulin resistance (IR) is associated with liver inflammatory diseases, but molecular mechanisms for the association remained elusive. IR is known to increase activity of forkhead box-containing protein O subfamily-1 (FOXO1), a transcription factor that was recently shown to enhance proinflammatory cytokine production in macrophages and adipocytes. Here we report that overexpression of constitutively active FOXO1 markedly increased chemokine ligand 20 (CCL20) expression and secretion in HepG2 hepatoma cells treated with TNF-α. The opposite was seen when endogenous FOXO1 was silenced. FOXO1 did not bind CCL20 promoter directly; instead, it potentiated CCL20 transcription through increasing the binding of p65/p50 heterodimer to a functional nuclear factor-κB site in the human CCL20 promoter. The conditional medium from TNF-α-treated HepG2 cells stimulated migration of human peripheral blood mononuclear cells. This stimulation was significantly enhanced when FOXO1 was overexpressed, and attenuated when FOXO1 was silenced. CCL20 antibody partly blocked the synergistic effect of FOXO1 and TNF-α on peripheral blood mononuclear cells migration. Additionally, TNF-α antagonizes the insulin/Akt signal transduction, thus leading to activation of FOXO1, which is capable of mediating a transcriptional activation role in response to TNF-α on CCL20 gene expression in HepG2 cells and promotes lymphocyte chemotaxis. Furthermore, we found that FOXO1 and CCL20 were coordinately up-regulated in the insulin resistant and inflammatory cell-infiltrated liver of db/db mice, an animal model that displayed hepatic and systemic low-grade inflammation. In conclusion, our data suggest that FOXO1 links IR to lymphocyte chemotaxis in the insulin-resistant hepatocytes and livers by amplifying nuclear factor-κB-dependent hepatic CCL20 production.
Hongming Miao; Yang Zhang; Zhongyan Lu; Liqing Yu; Lixia Gan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-01-12
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  26     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-02-27     Completed Date:  2012-06-22     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  423-37     Citation Subset:  IM    
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MeSH Terms
Base Sequence
Chemokine CCL20 / genetics,  metabolism*,  secretion
Forkhead Transcription Factors / genetics,  metabolism,  physiology*
Gene Expression Regulation
Hep G2 Cells
Inflammation / metabolism,  pathology
Insulin / physiology
Liver / metabolism
Lymphocytes / metabolism,  physiology*
Mice, Inbred C57BL
Mice, Obese
NF-kappa B p50 Subunit / metabolism*
Protein Binding
Response Elements
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factor RelA / metabolism*
Transcription, Genetic
Tumor Necrosis Factor-alpha / physiology
Grant Support
Reg. No./Substance:
0/CCL20 protein, human; 0/Chemokine CCL20; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Insulin; 0/NF-kappa B p50 Subunit; 0/Transcription Factor RelA; 0/Tumor Necrosis Factor-alpha

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

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