Overlapping Pathways Mediate the Opposing Actions of Tumor Necrosis Factor-α and Transforming Growth Factor-β on α2(I) Collagen Gene Transcription

Abstract

Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) are multifunctional peptides intimately involved in the process of extracellular matrix remodeling. We recently showed that TGF-beta stimulates the human alpha 2(I) collagen gene by increasing the affinity of an Sp1-containing transcriptional complex bound to an upstream sequence termed the TbRE (Inagaki, Y., Truter, S. and Ramirez, F. (1994) J. Biol. Chem. 269, 14828-14834). Here, we report that the TbRE-bound complex also mediates the inhibitory signal of TNF-alpha. Nuclear proteins from cells treated with TNF-alpha bind to the TbRE sequence substantially more strongly than those from untreated cells. Additionally, TNF-alpha increases binding of a second protein complex that recognizes the negatively cis-acting element located immediately next to the TbRE. Thus, we postulate that TNF-alpha counteracts the TGF-beta-elicited stimulation of collagen gene expression through overlapping nuclear signaling pathways. One modifies the TGF-beta-targeted transcriptional complex, probably by reducing its stimulatory effect on collagen transcription. The other acts on the binding of the adjacent factor, presumably by increasing its effectiveness in repressing the activity of the collagen promoter. The convergence of the TGF-beta and TNF-alpha pathways on the same sequence of the alpha 2(I) collagen promoter is yet another example of combinatorial gene regulation achieved through composite response elements.

Oncostatin M Stimulates Transcription of the Human α2(I) Collagen Gene via the Sp1/Sp3-binding Site

“…The reason for the discrepancy between these two studies is presently not clear. Furthermore, TNF-␣ has been shown to inhibit ␣2(I) collagen transcription via the same response element that mediates TGF-␤ stimulation (32,33). The response elements mediating modulation of ␣2(I) collagen promoter activity by other cytokines have not been reported.…”

S-Adenosylmethionine Blocks Collagen I Production by Preventing Transforming Growth Factor-β Induction of the COL1A2 Promoter

“…For the gel mobility shift assays, a probe was generated by digestion with BglII and BstXI (Ϫ378 to Ϫ183 bp) of the Ϫ378COL1A2-CAT plasmid, which contains the TGF␤-responsive element (11,12,31,32). This probe was end labeled with [␥-32 P]ATP and T4 kinase (Promega).…”

“…Addition of 30 M AdoMet for 24 h after transfection decreased the basal activity of both the Ϫ3500COL1A2-CAT and the Ϫ378COL1A2-CAT reporter vectors. It is interesting that AdoMet lowered CAT activity in cells transfected with the Ϫ378COL1A2-CAT construct, which contains the Ϫ378 to ϩ58 bp region that is essential for increased basal COL1A2 expression and responsiveness to oxidative stress and cytokines such as TNF␣ and TGF␤ (11,12,21,29,32,37).…”

“…Central to the development and progression of fibrosis are cytokines that are normally involved in matrix remodeling; among them, transforming growth factor-␤ (TGF␤) enhances collagen I production and inhibits the synthesis of proteolytic enzymes that catalyze extracellular matrix degradation while enhancing the expression of protease inhibitors (11,12). As a result, TGF␤ is believed to play a critical role in liver fibrosis.…”

Cooperation between SMAD and NF-κB in growth factor regulated type VII collagen gene expression

“…Speci®cally, we previously demonstrated that TGF-b has an additive, if not synergistic, e ect with pro-in¯ammatory cytokines, such as IL-1 or TNF-a, on type VII collagen gene expression, as measured at both protein and mRNA levels (Mauviel et al, 1994). In contrast, the e ects of TGF-b and TNF-a on type I collagen gene expression are antagonistic, TGF-b being a powerful activator of type I collagen gene promoters (both COL1A1 and COL1A2) while TNF-a exerts an inhibitory e ect (Varga et al, 1987;Inagaki et al, 1995;Chung et al, 1996).…”