Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins

Extracellular matrix (ECM) formation and remodeling are critical processes for proper morphogenesis, organogenesis, and tissue repair. The proinflamma tory cytokine tumor necrosis factor alpha (TNF-alpha) inhibits ECM accumula tion by stimulating the expression of matrix proteolytic enzymes and by dow nregulating the deposition of structural macromolecules such as type I coll agen. Stimulation of ECM degradation has been linked to prolonged activatio n of jun gene expression by the cytokine. Here we demonstrate that TNF-alph a inhibits transcription of the gene coding for the alpha 2 chain of type I collagen [alpha 2(I) collagen] in cultured fibroblasts by stimulating the synthesis and binding of repressive CCAAT/enhancer proteins (C/EBPs) to a p reviously identified TNF-alpha-responsive element, This conclusion was base d on the concomitant identification of C/EBP beta and C/EBP delta as TNF-al pha-induced factors by biochemical purification and expression library scre ening. It was further supported by the ability of the C/EBP-specific domina nt-negative (DN) protein to block TNF-alpha inhibition of alpha 2(I) collag en but not TNF-alpha stimulation of the MMP-13 protease. The DN protein als o blocked TNF-alpha downregulation of the gene coding for the alpha 1 chain of type I collagen. The study therefore implicates repressive C/EBPs in th e TNF-alpha-induced signaling pathway that controls ECM formation and remod eling.