Function of Rho-kinase in prostaglandin D2 -induced interleukin-6 synthesis in osteoblasts

• Published in: Prostaglandins, leukotrienes and essential fatty acids Vol. 79; no. 1; pp. 41 - 46
• Main Authors: Tokuda, Haruhiko, Takai, Shinji, Matsushima-Nishiwaki, Rie, Hanai, Yoshiteru, Adachi, Seiji, Minamitani, Chiho, Mizutani, Jun, Otsuka, Takanobu, Kozawa, Osamu
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier 01.07.2008
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; Advanced Basic Science; Amides - pharmacology; Animals; Anthracenes - pharmacology; Biological and medical sciences; Cells, Cultured; Dose-Response Relationship, Drug; Endocrinology & Metabolism; Endothelin-1 - pharmacology; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Imidazoles - pharmacology; Interleukin-6 - biosynthesis; Mice; Mitogen-Activated Protein Kinase 1 - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - drug effects; Mitogen-Activated Protein Kinase 3 - metabolism; Myosin-Light-Chain Kinase - drug effects; Myosin-Light-Chain Kinase - metabolism; Myosin-Light-Chain Phosphatase; Osteoblasts - drug effects; Osteoblasts - metabolism; p38 Mitogen-Activated Protein Kinases - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Prostaglandin D2 - pharmacology; Pyridines - pharmacology; rho-Associated Kinases - physiology; Structure-Activity Relationship; Vertebrates: endocrinology; Osteoarticular system; Interleukin 6; Rho kinase; Cytokine; Osteoblast; Biosynthesis; Bone; Prostaglandin D2
• DOI: 10.1016/j.plefa.2008.07.004
• ISSN: 0952-3278

Abstract We have previously reported that prostaglandin D2 (PGD2 ) stimulates interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether Rho-kinase is implicated in the PGD2 -stimulated IL-6 synthesis in MC3T3-E1 cells. PGD2 time-dependently induced the phosphorylation of myosin phosphatase targeting subunit (MYPT-1), a Rho-kinase substrate. Y27632, a specific Rho-kinase inhibitor, significantly reduced the PGD2 -stimulated IL-6 synthesis as well as the MYPT-1 phosphorylation. Fasudil, another inhibitor of Rho-kinase, suppressed the PGD2 -stimulated IL-6 synthesis. The PGD2 -stimulated IL-6 synthesis was reduced by PD98059, a MEK inhibitor, and SB203580, an inhibitor of p38 mitogen-activated protein (MAP) kinase, but not SP600125, an inhibitor of stress-activated protein kinase/c– Jun N-terminal kinase (SAPK/JNK). However, Y27632 and fasudil failed to affect the PGD2 -induced phosphorylation of p44/p42 MAP kinase. On the other hand, Y27632 as well as fasudil markedly attenuated the PGD2 -induced phosphorylation of p38 MAP kinase. In addition, PGD2 additively induced IL-6 synthesis in combination with endothelin-1 which induces IL-6 synthesis through p38 MAP kinase regulated by Rho-kinase. These results strongly suggest that Rho-kinase regulates PGD2 -stimulated IL-6 synthesis via p38 MAP kinase activation in osteoblasts.