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Tumor necrosis factor α down‐regulates expression of the α1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPβ‐ and C/EBPδ‐dependent mechanism
Author(s) -
Iraburu María J.,
DomínguezRosales José A.,
Fontana Luis,
Auster Anitra,
GarcíaTrevijano Elena R.,
CovarrubiasPinedo Amador,
RivasEstilla Ana María,
Greenwel Patricia,
Rojkind Marcos
Publication year - 2000
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/he.2000.5981
Subject(s) - tumor necrosis factor alpha , transcription factor , hepatic stellate cell , biology , microbiology and biotechnology , gene expression , promoter , ccaat enhancer binding proteins , cytokine , reporter gene , regulation of gene expression , transcription (linguistics) , gene , nuclear protein , biochemistry , endocrinology , immunology , linguistics , philosophy
Tumor necrosis factor α (TNF‐α) is one of the key cytokines of the acute phase response and of many inflammatory processes. This cytokine has several antifibrogenic actions and down‐regulates the expression of the type I collagen genes and induces the expression of metalloproteinases. Because TNF‐α directly antagonizes some fibrogenic actions of transforming growth factor β 1 (TGF‐β 1 ), we considered it important to map the cis ‐acting regulatory element of the α1(I) collagen ( col1a1 ) promoter involved in TNF‐α responsiveness in hepatic stellate cells (HSC), to investigate the transcription factors that bind to it, and to establish possible mechanisms by which TNF‐α down‐regulates its expression. In this article, we show the presence of a functional TNF‐α–responsive element (TaRE) in the −378 to −345 region of the col1a1 promoter. This element colocalizes with a previously reported TGF‐β 1 –responsive element. We further demonstrate that TNF‐α induces nuclear translocation and binding of transcriptional complexes containing p20C/EBPβ, p35C/EBPβ, and C/EBPδ to this sequence of the promoter. Transient overexpression of C/EBPδ or p20C/EBPβ, the natural dominant negative form of C/EBPβ in HSC, down‐regulated activity of a CAT reporter vector driven by −412 to +110 of the col1a1 promoter. Taken together, these data suggest that the −378 to −340 region of the col1a1 promoter is the site of convergence of different stimuli that ultimately modulate col1a1 gene transcription.