Methotrexate suppresses inflammatory agonist induced interleukin 6 synthesis in osteoblasts

• Published in: Journal of rheumatology Vol. 32; no. 5; p. 787
• Main Authors: Yoshida, Minoru, Kanno, Yosuke, Ishisaki, Akira, Tokuda, Haruhiko, Hirade, Kouseki, Nakajima, Keiichi, Katagiri, Yoshihiro, Shimizu, Katsuji, Kozawa, Osamu
• Format: Journal Article
• Language: English
• Published: Canada 01.05.2005
• Subjects: 3T3 Cells; Animals; Antirheumatic Agents - pharmacology; Carcinogens - pharmacology; Cells, Cultured; Dinoprost - pharmacology; Dinoprostone - pharmacology; Drug Interactions; Interleukin-1 - pharmacology; Interleukin-17 - pharmacology; Interleukin-6 - metabolism; Methotrexate - pharmacology; Mice; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Prostaglandin D2 - pharmacology; Tetradecanoylphorbol Acetate - pharmacology; Tumor Necrosis Factor-alpha - pharmacology; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0315-162X

Interleukin 6 (IL-6) is a pleiotropic cytokine that plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). In bone metabolism, it is known that IL-6 is produced and secreted by osteoblasts, and that IL-6 induces osteoclast formation and stimulates bone resorption. Various bone inflammatory agonists such as tumor necrosis factor-alpha (TNF-alpha), IL-1alpha, prostaglandin D2 (PGD2), PGE2, and PGF2alpha, which play important roles in the pathogenesis of RA, induce IL-6 synthesis in osteoblast-like MC3T3-E1 cells. Low dose methotrexate (MTX) is currently used for treatment of patients with RA. We investigated the effect of MTX on IL-6 synthesis induced by these agents in MC3T3-E1 cells. Cultured cells were pretreated with various doses of MTX, and then stimulated by these inflammatory agonists. The IL-6 in the conditioned medium was measured by IL-6 enzyme immunoassay. MTX significantly suppressed IL-6 synthesis stimulated by these agonists in a dose-dependent manner, although MTX alone had no effect on the levels of IL-6. In addition, MTX significantly inhibited the enhancement by IL-17 of TNF-alpha-stimulated IL-6 synthesis. MTX reduced the levels of IL-6 induced by 12-O-tetradecanoylphorbol 13-acetate, a direct activator of protein kinase C (PKC), suggesting that MTX inhibits PKC signals for IL-6 synthesis. MTX suppresses IL-6 synthesis stimulated by various inflammatory agonists in osteoblasts.