title: The p38 mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumor necrosis factor in osteoblasts.
abstract: The induction of interleukin-6 (IL-6), using a proinflammatory cytokine (tumor necrosis factor-alpha), was studied in a human osteoblast cell line (MG-63) in relation to p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB transcription factor. When added to MG-63 cells, tumor necrosis factor-alpha (TNF-alpha) had a stimulatory effect on the production of IL-6, and this elevation was significantly reduced by SB203580, a specific p38 MAPK inhibitor. In addition, the stimulation of IL-6 release was also reduced by pyrrolidine dithiocarbamate (PDTC) or NF-kappaB SN50, which has been reported to be a potent NF-kappaB inhibitor. Both the NF-kappaB inhibitors in the presence of SB203580 had a more inhibitory effect on IL-6 release. In this study, TNF-alpha stimulated NF-kappaB binding affinity as well as p38 MAP kinase activation, leading to the release of IL-6. However, the specific inhibitor of p38 MAPK, SB203580, had no effect on TNF-alpha-induced NF-kappaB activation and both NF-kappaB inhibitors failed to reduce the p38 MAPK activation in the TNF-alpha-stimulated osteoblasts. In addition, inhibition of p38 MAPK partially, but significantly, impaired TNF-alpha-regulated release of osteocalcin, an important differentiation marker in osteoblasts. These results strongly suggest that both p38 MAPK and NF-kappaB are required in TNF-alpha-induced IL-6 synthesis and that these two TNF-alpha-activated pathways can be primarily dissociated. Furthermore, p38 MAPK may play a significant role in differentiation in MG-63 cells.
authors.affiliation: Department of Dental Pharmacology and Wonkwang Dental Research Institute, College of Pharmacy, Center of Oriental Medicinal Science, Wonkwang University, Chonbuk, South Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Chae
authors.forename: S W
authors.initials: SW
authors.lastname: Chae
authors.forename: H Y
authors.initials: HY
authors.lastname: Chin
authors.forename: B G
authors.initials: BG
authors.lastname: Bang
authors.forename: S B
authors.initials: SB
authors.lastname: Cho
authors.forename: K S
authors.initials: KS
authors.lastname: Han
authors.forename: S C
authors.initials: SC
authors.lastname: Kim
authors.forename: K C
authors.initials: KC
authors.lastname: Tae
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
authors.forename: D E
authors.initials: DE
authors.lastname: Kim
authors.forename: M K
authors.initials: MK
authors.lastname: Im
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
authors.forename: J Y
authors.initials: JY
authors.lastname: Chang
authors.forename: Y M
authors.initials: YM
authors.lastname: Lee
authors.forename: H M
authors.initials: HM
authors.lastname: Kim
authors.forename: H H
authors.initials: HH
authors.lastname: Kim
authors.forename: Z H
authors.initials: ZH
authors.lastname: Lee
authors.forename: H R
authors.initials: HR
authors.lastname: Kim
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology*; D015675:Osteocalcin / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D016328:NF-kappa B; D010455:Peptides; D011725:Pyridines; D011759:Pyrrolidines; C118258:SN50 peptide; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D015675:Osteocalcin; C020972:pyrrolidine dithiocarbamic acid; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580