Varga J, Yufit T, Hitraya E, Brown R R
Division of Rheumatology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Adv Exp Med Biol. 1996;398:143-8. doi: 10.1007/978-1-4613-0381-7_23.
Interleukin-1 beta (IL-1 beta) 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-gamma inhibited. Type I collagen gene expression, and abrogated the effect of IL-1 beta on MMP expression. Interferon-gamma 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-gamma on matrix-degrading enzymes, exogenous tryptophan was added to tryptophan-depleted media, followed by stimulation of the cultures with IL-1 beta. Supplementation with tryptophan completely overcame the inhibitory effects of interferon-gamma on MMP mRNA expression and metalloproteinase secretion into the media. In contrast mRNA levels for Type I collagen remained profoundly depressed in interferon-gamma-treated cultures in spite of addition of exogenous tryptophan. These results indicate that oxidative tryptophan metabolism mediates the effects of interferon-gamma on MMP gene expression in human fibroblasts.
白细胞介素-1β（IL-1β）是诱导基质降解酶胶原酶和基质溶解素的强效信号。这些金属蛋白酶（MMP）在生理和病理结缔组织重塑中起关键作用，并且是治疗干预的潜在靶点。用γ干扰素处理人皮肤成纤维细胞可抑制I型胶原基因表达，并消除IL-1β对MMP表达的影响。γ干扰素还导致吲哚胺2,3-双加氧酶mRNA呈显著的剂量依赖性增加，从而使培养基中的色氨酸耗竭并使犬尿氨酸积累。为了研究色氨酸代谢在γ干扰素对基质降解酶作用中的作用，将外源性色氨酸添加到色氨酸耗尽的培养基中，然后用IL-1β刺激培养物。补充色氨酸完全克服了γ干扰素对MMP mRNA表达和金属蛋白酶分泌到培养基中的抑制作用。相反，尽管添加了外源性色氨酸，但在γ干扰素处理的培养物中I型胶原的mRNA水平仍然严重降低。这些结果表明，氧化性色氨酸代谢介导了γ干扰素对人成纤维细胞中MMP基因表达的影响。
