title: Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins.
abstract: Extracellular matrix (ECM) formation and remodeling are critical processes for proper morphogenesis, organogenesis, and tissue repair. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) inhibits ECM accumulation by stimulating the expression of matrix proteolytic enzymes and by downregulating the deposition of structural macromolecules such as type I collagen. Stimulation of ECM degradation has been linked to prolonged activation of jun gene expression by the cytokine. Here we demonstrate that TNF-alpha inhibits transcription of the gene coding for the alpha2 chain of type I collagen [alpha2(I) collagen] in cultured fibroblasts by stimulating the synthesis and binding of repressive CCAAT/enhancer proteins (C/EBPs) to a previously identified TNF-alpha-responsive element. This conclusion was based on the concomitant identification of C/EBPbeta and C/EBPdelta as TNF-alpha-induced factors by biochemical purification and expression library screening. It was further supported by the ability of the C/EBP-specific dominant-negative (DN) protein to block TNF-alpha inhibition of alpha2(I) collagen but not TNF-alpha stimulation of the MMP-13 protease. The DN protein also blocked TNF-alpha downregulation of the gene coding for the alpha1 chain of type I collagen. The study therefore implicates repressive C/EBPs in the TNF-alpha-induced signaling pathway that controls ECM formation and remodeling.
authors.affiliation: Brookdale Center, Department of Biochemistry, Mount Sinai School of Medicine, New York University, New York, New York 10029, USA.
authors.forename: P
authors.initials: P
authors.lastname: Greenwel
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: D
authors.initials: D
authors.lastname: Penkov
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Olive
authors.forename: J
authors.initials: J
authors.lastname: Moll
authors.forename: C
authors.initials: C
authors.lastname: Vinson
authors.forename: M
authors.initials: M
authors.lastname: Di Liberto
authors.forename: F
authors.initials: F
authors.lastname: Ramirez
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D024042:Collagen Type I; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen