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

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.