STUDIES ON THE EFFECTIVE REGULATION OF MATRIX METALLOPROTEINASES IN PHEUMATOID ARTHRITIS

1992年和1993年，为了建立类风湿性关节炎中参与基质降解的基质金属蛋白酶（MMPs）的有效调控方法，研究了白细胞介素1（IL-1）、IL-6和前列腺素E（PGE）对人滑膜成纤维细胞MMPs产生的确切作用。IL-6对人滑膜细胞的透明质酸、蛋白多糖等细胞外基质成分的代谢、纤溶酶原激活剂和前列腺素E2的产生无明显影响。IL-6可促进基质金属蛋白酶组织抑制因子（TIMP-1）的产生，但不影响MMP的产生。然而，在IL-1的存在下，IL-6增强了IL-1介导的MMPs的产生，表明IL-6被发现是炎症的促进剂。这些结果已发表在关节炎Rheumatol杂志上。三十五：1197-1201（1992），并且否定了IL-6可能是抗炎细胞因子的概念。吲哚美辛和双氯芬酸的环氧合酶抑制剂进一步增强了IL-1诱导的MMPs的产生，这种增强被发现是由于这些抑制剂的内源性PGE的抑制。炎症介质PGE 2作为抗炎因子抑制MMP的产生。因此，从这一点来看，环氧合酶抑制剂可能不适合作为抗类风湿药物，因此，合理的抗类风湿药物应设计成直接抑制IL-1和MMP的产生，和/或作为IL-1的抑制剂，如IL-1受体拮抗剂。

In 1992 and 1993, to establish the effective methods for the regulation of matrix metalloproteinases (MMPs) which participate the matrix degradation in rhuematoid arthritis, the exact roles of interleukin 1 (IL-1), IL-6 and prostaglandin E (PGE) on the production of MMPs in human synovial fibroblasts were investigated. Furthermore, effect of cyclooxygenase inhibitor of indomethacin on the MMPs production was also evaluated.IL-6 did not modulated the metabolism of extracellular matrix components including hyaluronic acid and proteoglycans, and plasmiogenactivator and PGE2 production in human synoviocytes. IL-6 accelerated the production of tissue inhibitor of metalloproteinases (TIMP-1) without affecting the MMPs production. Under presence of IL-1, however, IL-6 augmented the IL-1-mediated production of MMPs, indicating that IL-6 is found to be a promoter for the inflammation. These results have been published in the journal of Arthritis Rheumatol. 35 : 1197-1201 (1992), and denied the concept that IL-6 was likely to be an anti-inflammatory cytokine.In rheumatoid synovial cells, both PGE1 and PGE2 suppressed the IL-1-mediated production of MMPs. Cyclooxygenase inhibitor of indomethacin and diclofenac further augmented the IL-1-induced production of MMPs, and this augmentation was found to be resulted from the suppression by these inhibitors of endogenous PGE.In conclusion, in rheumatoid arthiritis IL-6 in addition to IL-1 was characterized as an inflammation promoting factor. PGE2 which is recognized as the inflammation mediator acted as an anti-inflammatory factor to suppress the MMP production. From this point of view, therefore, cyclooxygenase inhibitors might be unsuitable for anti-rheumatoid drugs, and thus reasonable anti-rheumatoid drugs should be designed to suppress directly the production of IL-1 and also MMPs, and/or to be a inhibitor for IL-1 such as the IL-1-receptor antagonist.