Inhibition of collagenase and stromelysin gene expression by interferon-γ in human dermal fibroblasts Is mediated in part via induction of tryptophan degradation

Abstract

The expression of the matrix-degrading enzymes collagenase and stromelysin is modulated by a variety of biologic and pharmacologic agents. IFN-γ has potent effects on metalloproteinase production and therefore may play an important role in preventing excessive connective tissue degradation during inflammation and repair. We investigated the mechanisms of collagenase and stromelysin regulation by IFN-γ in human dermal flbroblasts. IFN-γ (300 U/ml) prevented the stimulation of metalloproteinase gene expression by IL-1β. In addition, incubation of fibroblasts with IFN-γ resulted in a marked increase in cellular indoleamine 2,3- dioxygenase (IDO) mRNA, a > 90% depletion of tryptophan, and a corresponding > 30-fold increase in the tryptophan metabolite kynurenine in the culture media. Reducing the concentration of tryptophan from 25 μM to 0 markedly diminished the ability of fibroblasts to increase collagenase and stromelysin mRNA and collagenase production in response to IL-1β. Addition of exogenous tryptophan (25-50 μg/ml) to cultures that had been tryptophan depleted by pretreatment with IFN-γ for 48 h restored the flbroblast response to IL-1β or PMA, but had no effect on IFN-γ- induced HLA-DR α chain mRNA expression. These results indicate that inhibition of collagenase and stromelysin gene expression by IFN-γ in flbroblasts is associated with activation of IDO and enhanced cellular tryptophan metabolism. Tryptophan degradation and ensuing tryptophan depletion may account, at least in part, for the inhibitory effect of IFN-γ on metalloproteinase production in dermal flbroblasts.