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Title: 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: Iraburu, M.J.
Dominguez-Rosales, J.A.
Fontana, L.
Auster, A.
Garcia-Trevijano, E.R.
Covarrubias-Pinedo, A.
Rivas-Estilla, A.M.
Greenwel, P.
Rojkind, M.
Issue Date: 2000
Abstract: 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 β1 (TGF-β1), 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 downregulates 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-β1-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.
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