INHIBITION OF COLLAGENASE AND STROMELYSIN GENE-EXPRESSION BY INTERFERON-GAMMA IN HUMAN DERMAL FIBROBLASTS IS MEDIATED IN PART VIA INDUCTION OF TRYPTOPHAN DEGRADATION
INHIBITION OF COLLAGENASE AND STROMELYSIN GENE-EXPRESSION BY INTERFERON-GAMMA IN HUMAN DERMAL FIBROBLASTS IS MEDIATED IN PART VIA INDUCTION OF TRYPTOPHAN DEGRADATION
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DOI：
10.1172/jci118058
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发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
BROWN, RR
中科院分区：
文献类型：
--
作者：
VARGA, J;YUFIT, T;BROWN, RR
基质降解酶胶原酶和基质分解酶的表达受多种生物和药物的调节。干扰素-γ对金属蛋白酶的产生有很强的作用，因此在防止炎症和修复过程中过度的结缔组织降解中可能起重要作用。干扰素-γ(300U/ml)可阻断IL-1β对金属蛋白酶基因表达的刺激作用。此外，与干扰素-γ共同孵育成纤维细胞后，细胞吲哚胺2，3-双加氧酶(IDO)基因表达显著增加，色氨酸耗竭达90%，培养上清液中色氨酸代谢产物犬尿氨酸含量相应增加30倍，将色氨酸浓度从25mM降至0，可显著降低成纤维细胞对IL-1β的反应能力，使其增加胶原酶和基质分解酶mRNA及胶原酶产量。加入外源性色氨酸(25~50 mU g/ml)可恢复培养细胞对IL-1β或PMA的反应，但对干扰素-γ诱导的人类白细胞抗原-DRα链基因表达无影响。这些结果表明，干扰素-γ抑制成纤维细胞中胶原酶和基质分解酶基因的表达与激活IDO、促进细胞色氨酸代谢、色氨酸降解以及随后的色氨酸耗竭有关，这可能是干扰素-γ抑制真皮成纤维细胞金属蛋白酶产生的至少部分原因。
The expression of the matrix-degrading enzymes collagenase and stromelysin is modulated by a variety of biologic and pharmacologic agents. IFN-gamma 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-gamma in human dermal fibroblasts. IFN-gamma (300 U/ml) prevented the stimulation of metalloproteinase gene expression by IL-1 beta. In addition, incubation of fibroblasts with IFN-gamma 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 mu M to 0 markedly diminished the ability of fibroblasts to increase collagenase and stromelysin mRNA and collagenase production in response to IL-1 beta. Addition of exogenous tryptophan (25-50 mu g/ml) to cultures that had been tryptophan depleted by pretreatment with IFN-gamma for 48 h restored the fibroblast response to IL-1 beta or PMA, but had no effect on IFN-gamma-induced HLA-DR alpha chain mRNA expression, These results indicate that inhibition of collagenase and stromelysin gene expression by IFN-gamma in fibroblasts 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-gamma on metalloproteinase production in dermal fibroblasts.