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J Biol Chem, Vol. 275, Issue 20, 15220-15225, May 19, 2000

Tumor Necrosis Factor  Suppresses the Induction of Connective Tissue Growth Factor by Transforming Growth Factor- in Normal and Scleroderma Fibroblasts^*

David J. Abraham, Xu Shiwen, Carol M. Black, Susan Sa^§, Yili Xu^§, and Andrew Leask^§¶

From the  Center for Rheumatology, Royal Free and University College Medical School, Rowland Hill St., London W3 PF, United Kingdom and ^§ FibroGen, Inc., South San Francisco, California 94080

Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders, presumably secondary to the activation and production of transforming growth factor- (TGF-), a key inducer of fibroblast proliferation and matrix synthesis. The CTGF gene promoter has a TGF- response element that regulates its expression in fibroblasts but not epithelial cells or lymphocytes. Recent studies have shown that the macrophage-produced cytokine tumor necrosis factor  (TNF) is necessary to promote inflammation and to induce genes, such as matrix metalloproteinases, involved with the early stages of wound healing. In this study, we examined the ability of TNF to modulate CTGF gene expression. TNF was found to suppress the TGF--induced expression of CTGF protein in cultured normal fibroblasts. The activity of TNF was blocked by NF-B inhibitors. We showed that sequences between 244 and 166 of the CTGF promoter were necessary for both TGF- and TNF to modulate CTGF expression. There was a constitutive expression of CTGF by scleroderma fibroblasts that was increased by TGF- treatment. Although TNF was able to repress TGF--induced CTGF and collagen synthesis both in normal and scleroderma skin fibroblasts, fibroblasts cultured from scleroderma patients were more resistant to TNF as TNF was unable to suppress the basal level of CTGF expression in scleroderma fibroblasts. Thus, we suspect that the high level of constitutive CTGF expression in scleroderma fibroblasts and its inability to respond to negative regulatory cytokines may contribute to the excessive scarring of skin and internal organs in patients with scleroderma.

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