| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1993: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1992: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
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.
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