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-β (TGF-β) and tumor necrosis factor-α (TNF-α) are multifunctional peptides intimately involved in the process of extracellular matrix remodeling. We recently showed that TGF-β stimulates the human α2(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-α. Nuclear proteins from cells treated with TNF-α bind to the TbRE sequence substantially more strongly than those from untreated cells. Additionally, TNF-α 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-α counteracts the TGF-β-elicited stimulation of collagen gene expression through overlapping nuclear signaling pathways. One modifies the TGF-β-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-β and TNF-α pathways on the same sequence of the α2(I) collagen promoter is yet another example of combinatorial gene regulation achieved through composite response elements.