title: Interleukin (IL)-17 enhances tumor necrosis factor-alpha-stimulated IL-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts.
abstract: Inflammatory cytokines are well known to play crucial roles in the pathogenesis of rheumatoid arthritis. Among them, interleukin (IL)-17 is a cytokine that is mainly synthesized by activated T cells and its receptors are present in osteoblasts. The synthesis of IL-6, known to stimulate osteoclastic bone resorption, is reportedly responded to bone resorptive agents such as tumor necrosis factor-alpha (TNF-alpha) in osteoblasts. It has been reported that IL-17 enhances TNF-alpha-stimulated IL-6 synthesis in osteoblast-like MC3T3-E1 cells. We previously showed that sphingosine 1-phosphate (S1-P) mediates TNF-alpha-stimulated IL-6 synthesis in these cells. In the present study, we investigated the mechanism of IL-17 underlying enhancement of IL-6 synthesis in MC3T3-E1 cells. IL-17 induced phosphorylation of p38 mitogen-activated protein (MAP) kinase. SB203580 and PD169316, specific inhibitors of p38 MAP kinase, significantly reduced the enhancement by IL-17 of TNF-alpha-stimulated IL-6 synthesis. IL-17 also amplified S1-P-stimulated IL-6 synthesis, and the amplification by IL-17 was suppressed by SB203580. Anisomycin, an activator of p38 MAP kinase, which alone had no effect on IL-6 level, enhanced the IL-6 synthesis stimulated by TNF-alpha. SB203580 and PD169316 inhibited the amplification by anisomycin of the TNF-alpha-induced IL-6 synthesis. Taken together, our results strongly suggest that IL-17 enhances TNF-alpha-stimulated IL-6 synthesis via p38 MAP kinase activation in osteoblasts.
authors.affiliation: Department of Internal Medicine, Chubu National Hospital, National Institute for Longevity Sciences, Obu, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kanno
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
authors.forename: Motoki
authors.initials: M
authors.lastname: Takenaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Harada
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D020381:Interleukin-17; D015850:Interleukin-6; D008246:Lysophospholipids; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; D013110:Sphingosine; C093642:SB 203580