Document Detail


Ethanol augments RANTES/CCL5 expression in rat liver sinusoidal endothelial cells and human endothelial cells via activation of NF-kappa B, HIF-1 alpha, and AP-1.
MedLine Citation:
PMID:  19828633     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic alcohol consumption leads to liver inflammation and cirrhosis. Alcoholic liver disease patients have increased levels of hepatic RANTES/CCL5. However, less is known about the molecular mechanisms for ethanol-induced RANTES up-regulation. In this study, we observed that liver sinusoidal endothelial cells derived from ethanol-fed rats (E-rLSECs) showed severalfold increases in RANTES and hypoxia-inducible factor 1alpha (HIF-1alpha) mRNAs compared with control rLSECs (C-rLSECs). Similar effects were seen in acute ethanol treatment of isolated rLSECs and human dermal microvascular endothelial cells. Ethanol-induced RANTES mRNA expression required ethanol metabolism, p38 MAPK, HIF-1alpha, and JNK-2, but not JNK-1. EMSA experiments showed increased HIF-1alpha binding to wild-type hypoxia response elements (HREs; -31 to -9 bp) within the RANTES promoter in response to ethanol. RANTES promoter analysis showed that cis elements proximal to the transcription start site, HRE-1 (nt -22 to -19), HRE-2 (nt -32 to -29), and AP-1 (nt -250 to -244) were required for ethanol-mediated RANTES expression. These results were corroborated by chromatin immunoprecipitation assays showing augmented HIF-1alpha binding to HRE-1. Additionally, promoter analysis revealed c-Jun, c-Jun/c-Fos, and JunD, but not JunB, bound to the AP-1 site of the RANTES promoter. Ethanol-mediated activation of NF-kappaB led to HIF-1alpha activation and concomitant RANTES expression. Plasma of ethanol-fed c-Jun(flox/flox)-Mx-1-Cre mice showed attenuated levels of RANTES compared with ethanol-fed control mice, supporting the role of c-Jun in ethanol-induced RANTES expression. Our studies showed that ethanol-mediated RANTES/CCL5 expression occurs via HIF-1alpha activation independently of hypoxia. The identification of HIF-1alpha and AP-1 in ethanol-induced RANTES expression provides new strategies to ameliorate ethanol-induced inflammatory responses.
Authors:
Samantha M Yeligar; Keigo Machida; Hidekazu Tsukamoto; Vijay K Kalra
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-10-14
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  183     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-21     Completed Date:  2009-12-09     Revised Date:  2014-11-02    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5964-76     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Chemokine CCL5 / biosynthesis*
Endothelial Cells / drug effects,  immunology,  metabolism*
Endothelium, Vascular / cytology,  drug effects,  immunology,  metabolism*
Ethanol / administration & dosage,  pharmacology*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*,  physiology
Liver / blood supply,  cytology,  drug effects,  metabolism*
Male
Mice
Mice, Knockout
Mice, Transgenic
NF-kappa B / metabolism*,  physiology
Proto-Oncogene Proteins c-jun / deficiency,  genetics
Rats
Rats, Wistar
Transcription Factor AP-1 / metabolism*,  physiology
Up-Regulation / drug effects,  immunology
Grant Support
ID/Acronym/Agency:
CA108302/CA/NCI NIH HHS; P30 DK048522/DK/NIDDK NIH HHS; P30-DK048522/DK/NIDDK NIH HHS; P50 AA011999/AA/NIAAA NIH HHS; P50-AA011999/AA/NIAAA NIH HHS; R24 AA012885/AA/NIAAA NIH HHS; R24-AA012885/AA/NIAAA NIH HHS; T32 AA007578/AA/NIAAA NIH HHS; T32-AA07578/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/Chemokine CCL5; 0/Hif1a protein, rat; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/NF-kappa B; 0/Proto-Oncogene Proteins c-jun; 0/Transcription Factor AP-1; 3K9958V90M/Ethanol
Comments/Corrections

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