Effect of a benzylidene derivative, a novel antirheumatic agent, on IL-1 production.
3,4-Diacetoxy benzylidene diacetate (ACP) is a prodrug of protocatechualdehyde (PAL). PAL significantly inhibited interleukin-1 (IL-1) production and release in human monocytes in a dose dependent fashion under lipopolysaccharide (LPS) stimulation. ACP showed inhibitory effects on cartilage destruction of the femoral condyles induced by adjuvant arthritis in vivo in a significant and dose dependent fashion. To clarify the mechanism of action of ACP on rat adjuvant arthritis, we investigated the effects of PAL, a metabolite of ACP, on IL-1 production using synovial cell cultures derived from patients with rheumatoid arthritis. PAL significantly inhibited the IL-1 beta production induced by IL-1 alpha or PMA without inhibition of total protein synthesis and cytotoxicity. A protein kinase C (PKC) inhibitor, staurosporine, also suppressed the IL-1 beta production induced by IL-1 alpha or PMA, suggesting that the PKC pathway plays an important role in IL-1 alpha-induced IL-1 beta production. The calcium ionophore A23187 (A23187) potentiated the IL-1 beta production induced by IL-1 alpha. Whereas PAL slightly inhibited under these conditions, it was not statistically significant. These results suggest that PAL has a favourable action on cartilage destruction through the inhibition of IL-1 production induced by the modification of the PKC pathway.
Watanabe
K
K
Biomedical Research Laboratory, Kureha Chemical Industry Co., Ltd, Tokyo, Japan.
Hayashi
H
H
Mori
Y
Y
D000085:Acetates / Q000494:pharmacology*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001547:Benzaldehydes / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002357:Cartilage Diseases / Q000517:prevention & control; D002396:Catechols / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D009000:Monocytes / Q000187:drug effects; D011355:Prodrugs / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D019311:Staurosporine; D013585:Synovitis / Q000188:drug therapy
D000085:Acetates; D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001547:Benzaldehydes; D001597:Benzylidene Compounds; D002396:Catechols; D007375:Interleukin-1; D011355:Prodrugs; C005581:protocatechualdehyde; C084186:3,4-diacetoxybenzylidene diacetate; D011493:Protein Kinase C; D019311:Staurosporine