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, 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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
KE298 inhibits aberrant synovial cell functions of patients with RA by downregulating gene transcription, suggesting clinical application and usefulness of this new DMARD.
Sakane
T
T
Department of Immunology, St. Marianna University School of Medicine, Kawasaki, Japan.
Suzuki
N
N
Hirose
Y
Y
Miura
K
K
Wakisaka
S
S
Nagafuchi
H
H
Ichino
M
M
Tomita
T
T
Hashimoto
H
H
Ochi
T
T
Mihara
S
S
D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1; D010666:Phenylpropionates / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018501:Antirheumatic Agents; D015850:Interleukin-6; D010666:Phenylpropionates; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D017364:Collagenases; D020781:Matrix Metalloproteinase 1; C078547:esonarimod