Suppressive effects of the new antirheumatic drug KE-298 on TNF alpha-induced production of matrix metalloproteinases but not of tissue inhibitor-1 of metalloproteinases in human rheumatoid synoviocytes.
KE-298 is a novel antirheumatic drug which suppresses various animal models of arthritis by inhibiting the production of inflammatory cytokines. In a phase II study of rheumatoid arthritis patients, ingestion of KE-298 led to significant improvements in the Lansbury index. The objective of the present study was to clarify the effects of KE-298 against synovium functions, using rheumatoid arthritis synoviocytes. We investigated the effects of KE-298 on the production of matrix metalloproteinases and tissue inhibitor-1 of metalloproteinases and bone absorptive mediators including interleukin (IL)-6 and prostaglandin (PG) E2 in tumor necrosis factor (TNF)-alpha-stimulated rheumatoid arthritis synoviocytes. Rheumatoid arthritis synoviocytes were obtained from knee joints of rheumatoid arthritis patients and type B fibroblast-like synoviocytes were stimulated with TNF-alpha, with or without KE-298. The contents of metalloproteinases and tissue inhibitor-1 of metalloproteinases and IL-6 and PGE2 in culture media were measured by enzyme-linked immunosorbent assay. KE-298 significantly suppressed TNF-alpha-induced production of promatrix metalloproteinase-1 and IL-6, in a dose-dependent manner, but not that of tissue inhibitor-1 of metalloproteinases. The potential of KE-298 to suppress the production of matrix metalloproteinase-1 and IL-6 may explain its efficacy on rheumatoid arthritis.
Institute of Medical Science, St. Marianna University, School of Medicine, Kanagawa, Japan. s15385@ccm.taisho.co.jp
S
S
Takahashi
T
T
Inoue
M
M
Higaki
Y
Y
Mizushima
D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D010666:Phenylpropionates / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D018501:Antirheumatic Agents; D015850:Interleukin-6; D010666:Phenylpropionates; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases; D015232:Dinoprostone; C078547:esonarimod