Linked Life Data

19828633

Source:http://linkedlifedata.com/resource/pubmed/id/19828633

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2009-10-21
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1550-6606
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
183
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5964-76
pubmed:meshHeading
pubmed-meshheading:19828633-Animals, pubmed-meshheading:19828633-Cell Line, pubmed-meshheading:19828633-Chemokine CCL5, pubmed-meshheading:19828633-Endothelial Cells, pubmed-meshheading:19828633-Endothelium, Vascular, pubmed-meshheading:19828633-Ethanol, pubmed-meshheading:19828633-Humans, pubmed-meshheading:19828633-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:19828633-Liver, pubmed-meshheading:19828633-Male, pubmed-meshheading:19828633-Mice, pubmed-meshheading:19828633-Mice, Knockout, pubmed-meshheading:19828633-Mice, Transgenic, pubmed-meshheading:19828633-NF-kappa B, pubmed-meshheading:19828633-Proto-Oncogene Proteins c-jun, pubmed-meshheading:19828633-Rats, pubmed-meshheading:19828633-Rats, Wistar, pubmed-meshheading:19828633-Transcription Factor AP-1, pubmed-meshheading:19828633-Up-Regulation
pubmed:year
2009
pubmed:articleTitle
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.
pubmed:affiliation
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural