Mechanisms of KE298, 2-acetylthiomethyl-3-(4-methylbenzoyl) propionic acid, to suppress abnormal synovial cell functions in patients with rheumatoid arthritis.

Abstract

2-Acetylthiomethyl-3-(4-methylbenzoyl) propionic acid, KE298, 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 disease modifying antirheumatic drug (DMARD). We analyzed effects of KE298 on synovial fibroblast-like cells in patients with RA to obtain insight into the clinical application of this medication. RA synovial fibroblast-like cells were co-cultured with KE298 at 10(-4)-10(-5) M in the presence or absence of tumor necrosis factor-alpha 2 ng/ml, and their subsequent proliferative responses and proinflammatory cytokine and matrix metalloproteinase (MMP) production at the mRNA and protein levels were measured. Effects of KE298 on MMP-1 gene transcription and AP-1 transcription factor expression of RA synovial cells were studied by chloramphenicol acetyltransferase assay and gel shift assay, respectively. KE298 inhibited proliferation of RA synovial cells, proinflammatory cytokine production, and MMP-1 production mainly by reducing their transcription via downmodulation of AP-1 transcription factor. KE298 inhibits aberrant synovial cell functions of patients with RA by downregulating gene transcription, suggesting clinical application and usefulness of this new DMARD.