Blockade of the p38 mitogen-activated protein kinase pathway inhibits inducible nitric oxide synthase and interleukin-6 expression in MC3T3E-1 osteoblasts.
Treatment of MC3T3E-1 osteoblast cultures with combined interferon- gamma(IFN- gamma), lipopolysaccharide (LPS) and tumor necrosis factor- alpha(TNF- alpha) induces expressions of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6), resulting in sustained releases of large amounts of nitric oxide and IL-6. However IFN- gamma, LPS and TNF- alpha individually induces non-detectable or small amounts of NO and IL-6 in MC3T3E-1 osteoblasts. The role of mitogen-activated protein kinase (MAPK) activation in the early intracellular signal transduction involved in iNOS and IL-6 transcription in the combined agents-stimulated osteoblasts has been investigated. The p38 MAPK pathway is specifically involved in the combined agents-induced NO and IL-6 release, since NO and IL-6 release in the presence of a specific inhibitor of p38 MAPK, 4-(4-fluorophenyl)-2-(4-metylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580), are significantly diminished. In contrast, PD98059, a specific inhibitor of MEK1, had no effect on NO and IL-6 release. Northern blot analysis showed that the p38 MAPK pathway controlled iNOS and IL-6 transcription levels. These data suggest that p38 MAPK plays an important role in the secretion of NO and IL-6 in LPS/IFN- gamma or TNF- alpha /IFN- gamma -treated MC3T3E-1 osteoblasts.
Chae
H J
HJ
Department of Dental Pharmacology and Wonkwang Dental Research Institute, Wonkwang University, Iksan, South Korea.
Kim
S C
SC
Chae
S W
SW
An
N H
NH
Kim
H H
HH
Lee
Z H
ZH
Kim
H R
HR
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010006:Osteoblasts / Q000201:enzymology* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors
D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C496317:Nos2 protein, mouse; C093642:SB 203580