MECHANISMS OF KE298, 2-ACETYLTHIOMETHYL-3-(4-METHYLBENZOYL) PROPIONIC-ACID, TO SUPPRESS ABNORMAL SYNOVIAL CELL FUNCTIONS IN PATIENTS WITH RHEUMATOID-ARTHRITIS

Objective, 2-acetylthiomethyl-3-(4-methylbenzoyl) propionic acid, KE29 8, a derivative or propionic acid developed in Japan has been shown to be effective for suppressing disease activity of rheumatoid arthritis (RA) in clinical trials in Japan. It is thus a candidate as a new dis ease modifying antirheumatic drug (DMARD), We analyzed effects of KE29 8 on synovial fibroblast-like cells in patients with RA to obtain insi ght into the clinical application of this medication, Methods. RA syno vial fibroblast-like cells were co-cultured with KE298 at 10(-4)simila r to 10(-5) M in the presence or absence of tumor necrosis factor-alph a 2 ng/ml, and their subsequent proliferative responses and proinflamm atory cytokine and matrix metalloproteinase (MMP) production at the mR NA and protein levels were measured, Effects of KE298 on MMP-1 gene tr anscription and AP-1 transcription factor expression of RA synovial ce lls were studied by chloramphenicol acetyltransferase assay and gel sh ift assay, respectively. Results. KE298 inhibited proliferation of RA synovial cells, proinflammatory cytokine production, and MMP-1 product ion mainly by reducing their transcription via downmodulation of AP-1 transcription factor. Conclusion. KE298 inhibits aberrant synovial cel l functions of patients with RA by downregulating gene transcription, suggesting clinical application and usefulness of this new DMARD.