title: Zinc suppresses IL-6 synthesis by prostaglandin F2alpha in osteoblasts: inhibition of phospholipase C and phospholipase D.
abstract: We previously reported that prostaglandin F2alpha (PGF2alpha) induces phosphoinositide hydrolysis by phospholipase C and phosphatidylcholine hydrolysis by phospholipase D through heterotrimeric GTP-binding protein, resulting in the activation of protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells and that PGF2alpha stimulates the synthesis of interleukin-6 (IL-6) via PKC-dependent p44/p42 mitogen-activated protein (MAP) kinase activation. In the present study, we investigated whether zinc affects the PGF2alpha-induced IL-6 synthesis in these cells. Zinc complex of l-carnosine (l-CAZ) dose-dependently suppressed the PGF2alpha-stimulated IL-6 synthesis. In addition, zinc alone reduced the IL-6 synthesis. L-CAZ suppressed the PGF2alpha-induced p44/p42 MAP kinase phosphorylation. However, the p44/p42 MAP kinase phosphorylation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator of PKC, or NaF, a direct activator of GTP-binding protein, was not affected by l-CAZ. l-CAZ reduced the PGF2alpha-stimulated formation of inositol phosphates and choline. However, l-CAZ did not affect the formation of inositol phosphates or choline induced by NaF. These results strongly suggest that zinc reduces PGF2alpha-induced IL-6 synthesis via suppression of phosphoinositide-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D in osteoblasts.
authors.affiliation: Department of Pharmacology, Gifu University School of Medicine, Gifu 500-8705, Japan.
authors.forename: Daijiro
authors.initials: D
authors.lastname: Hatakeyama
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shibata
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Uematsu
mesh_terms: D000818:Animals; D002336:Carnosine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D002794:Choline / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007295:Inositol Phosphates / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D012969:Sodium Fluoride / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*; D019287:Zinc Sulfate / Q000494:pharmacology
chemical_list: D007295:Inositol Phosphates; D015850:Interleukin-6; D019287:Zinc Sulfate; D002336:Carnosine; D012969:Sodium Fluoride; D015237:Dinoprost; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D010739:Phospholipase D; D015032:Zinc; D002794:Choline; D013755:Tetradecanoylphorbol Acetate