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Molecular and Cellular Biology, February 2000, p. 912-918, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Tumor Necrosis Factor Alpha Inhibits Type I Collagen Synthesis through Repressive CCAAT/Enhancer-Binding Proteins

Patricia Greenwel,1 Shizuko Tanaka,1 Dmitri Penkov,1 Wen Zhang,1 Michelle Olive,2,dagger Jonathan Moll,2 Charles Vinson,2 Maurizio Di Liberto,3 and Francesco Ramirez1,*

Brookdale Center, Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York University, New York, New York 100291; Laboratory of Biochemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922; and Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 100213

Received 20 August 1999/Returned for modification 16 September 1999/Accepted 5 November 1999

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 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 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 alpha 2(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 alpha 1 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.

* Corresponding author. Mailing address: Brookdale Center in the Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York University, New York, NY 10029. Phone: (212) 241-7984. Fax: (212) 722-5999. E-mail: ramirf01{at}doc.mssm.edu.

dagger Present address: Unité INSERM 441, 33600 Pessac, France.

Molecular and Cellular Biology, February 2000, p. 912-918, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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