Tumor necrosis factor alpha down-regulates expression of the alpha 1(I) collagen gene in rat hepatic stellate cells through a p20C/EBP beta- and C/EBP delta-dependent mechanism

Tumor necrosis factor alpha (TNF-alpha) is one of the key cytokines of the acute phase response and of many inflammatory processes. This cytokine has several antifibrogenic actions and do down-regulates the expression of the type I collagen genes and induces the expression of metalloproteinases. Bec ause TNF-alpha directly antagonizes some fibrogenic actions of transforming growth factor beta(1) (TGF-beta(1)), we considered it important to map the cis-acting regulatory element of the alpha 1(I) collagen (col1a1) promoter involved in TNF-alpha responsiveness in hepatic stellate cells (HSC), to i nvestigate the transcription factors that bind to it, and to establish poss ible mechanisms by which TNF-alpha downregulates its expression. In this ar ticle, we show the presence of a functional TNF-alpha-responsive element (T aRE) in the -378 to -345 region of the col1a1 promoter, This element coloca lizes with a previously reported TGF-beta(1)-responsive element, We further demonstrate chat TNF-alpha induces nuclear translocation and binding of tr anscriptional complexes containing p20C/ET3P beta, p35C/EBP beta, and C/EBP delta to this sequence of the promoter. Transient overexpression of C/EBP delta or p20C/EBP beta, the natural dominant negative form of C/EBP beta in HSC, down-regulated activity of a CAT reporter vector driven by -412 to +1 10 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 differ ent stimuli chat ultimately modulate col1a1 gene transcription.