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Endocrinology Vol. 140, No. 11 5120-5125
Copyright © 1999 by The Endocrine Society

ARTICLES

Mitogen-Activated Protein (MAP) Kinases Are Involved in Interleukin-1 (IL-1)-Induced IL-6 Synthesis in Osteoblasts: Modulation Not of p38 MAP Kinase, But of p42/p44 MAP Kinase by IL-1-Activated Protein Kinase C1

Masaichi Miwa, Osamu Kozawa, Haruhiko Tokuda and Toshihiko Uematsu

Department of Internal Medicine, Gifu Social Insurance Hospital (M.M.), Kani, Gifu 509-0206; the Department of Pharmacology, Gifu University School of Medicine (O.K., T.U.), Gifu 500-8705; and the Department of Internal Medicine, Chubu National Hospital: National Institute for Longevity Sciences (H.T.), Obu, Aichi 474-8511, Japan

Address all correspondence and requests for reprints to: Dr. Osamu Kozawa, Department of Pharmacology, Gifu University School of Medicine, Gifu 500-8705, Japan.

We previously reported that interleukin-1{alpha} (IL-1{alpha})-induced activation of protein kinase C (PKC) via phosphatidylcholine-specific phospholipase C (PC-PLC) limits IL-6 synthesis induced by IL-1{alpha} itself in osteoblast-like MC3T3-E1 cells. In the present study, we further investigated the mechanism behind IL-1{alpha}-induced IL-6 synthesis in MC3T3-E1 cells. IL-1{alpha} time-dependently stimulated the phosphorylation of both p42/p44 mitogen-activated protein (MAP) kinase and p38 MAP kinase. PD98059, a specific inhibitor of the upstream kinase that activates p42/p44 MAP kinase, inhibited the IL-1{alpha}-induced IL-6 synthesis as well as the phosphorylation of p42/p44 MAP kinase induced by IL-1{alpha}. SB203580, a specific inhibitor of p38 MAP kinase, also reduced both the phosphorylation of p38 MAP kinase and the IL-6 synthesis. 1-Oleoyl-2-acetylglycerol, an activator of PKC, suppressed the IL-1{alpha}-induced IL-6 synthesis. Calphostin C, a specific inhibitor of PKC, or D-609, a specific inhibitor of PC-PLC, significantly enhanced the IL-1{alpha}-induced phosphorylation of p42/p44 MAP kinase without affecting the phosphorylation of p38 MAP kinase. The phosphorylation of p42/p44 MAP kinase by IL-1{alpha} was markedly increased in PKC-down-regulated MC3T3-E1 cells. Neither 12-O-tetradecanoylphorbol-13-acetate, known to be an activator of PKC, nor 1-oleoyl-2-acetylglycerol affected the phosphorylation of p38 MAP kinase induced by IL-1{alpha}. These results strongly suggest that IL-1{alpha}-induced IL-6 synthesis is mediated via activations of both p42/p44 MAP kinase and p38 MAP kinase in osteoblasts, and that PKC activated by IL-1{alpha} itself negatively regulates IL-6 synthesis at a point upstream from p42/p44 MAP kinase.




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