Control of Extracellular Matrix Degradation by Interferon-γ: The Tryptophan Connection

J. Varga*, T. Yufit, E. Hitraya, R. R. Brown

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Interleukin-1β (IL-1β) is a potent signal for the induction of the matrix-degrading enzymes collagenase and stromelysin. These metalloproteinases (MMP) play a critical role in physiologic and pathologic connective tissue remodeling, and are potential targets for therapeutic manipulation. Treatment of human dermal fibroblasts with interferon-γ inhibited Type I collagen gene expression, and abrogated the effect of IL-1β on MMP expression. Interferon-γ also caused a dramatic dose-dependent increase in indoleamine 2,3-dioxygenase mRNA, with consequent depletion of tryptophan and accumulation of kynurenine in the culture media. To examine the role of tryptophan metabolism in the effects of interferon-γ on matrix-degrading enzymes, exogenous tryptophan was added to tryptophan-depleted media, followed by stimulation of the cultures with IL-1β. Supplementation with tryptophan completely overcame the inhibitory effects of interferon-γ on MMP mRNA expression and metalloproteinase secretion into the media. In contrast, mRNA levels for Type I collagen remained profoundly depressed in interferon-γ-treated cultures in spite of addition of exogenous tryptophan. These results indicate that oxidative tryptophan metabolism mediates the effects of interferon-γ on MMP gene expression in human fibroblasts.

Original languageEnglish (US)
Pages (from-to)143-148
Number of pages6
JournalAdvances in experimental medicine and biology
Volume398
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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