title: Involvement of MAP kinases in lipopolysaccharide-induced histamine production in RAW 264 cells.
abstract: Roles of mitogen-activated protein (MAP) kinases in lipopolysaccharide (LPS)-induced production of histamine in the mouse macrophage-like cell line RAW 264 were analyzed. Incubation of RAW 264 cells in the presence of LPS increased histamine levels in the conditioned medium in a concentration- and time-dependent manner. The levels of histidine decarboxylase (HDC) mRNA and the 74-kDa HDC protein were also increased at 4 to 8 h and 8 to 12 h, respectively. LPS elicited the phosphorylation of p44/42 MAP kinase, p38 MAP kinase, and c-Jun N-terminal kinase (JNK). The MAP kinase-Erk kinase 1 inhibitor U0126 (0.1-10 microM) suppressed the LPS-induced phosphorylation of p44/42 MAP kinase, and inhibited the LPS-induced production of histamine and expression of the HDC mRNA and 74-kDa HDC protein in a concentration-dependent manner. The JNK inhibitor SP600125 (3-30 microM) suppressed the LPS-induced phosphorylation of c-Jun, and inhibited the LPS-induced production of histamine and expression of the HDC mRNA and 74-kDa protein in a concentration-dependent manner. Combined treatment with U0126 (0.3 microM) and SP600125 (10 microM) inhibited the LPS-induced production of histamine additively. The p38 MAP kinase inhibitor SB203580 (0.1-10 microM) partially inhibited the LPS-induced production of histamine. These findings suggest that LPS increases histamine production in RAW 264 cells by inducing the expression of the 74-kDa HDC protein, and that the LPS-induced expression of HDC is up-regulated at the transcriptional level by MAP kinases, especially p44 MAP kinase and JNK.
authors.affiliation: Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan. hirasawa@mail.pharm.tohoku.ac.jp
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Hirasawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Torigoe
authors.forename: Ryohko
authors.initials: R
authors.lastname: Ohgawara
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohuchi
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006632:Histamine / Q000096:biosynthesis*; D006640:Histidine Decarboxylase / Q000032:analysis / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D000873:Anthracenes; D002070:Butadienes; D007093:Imidazoles; D008070:Lipopolysaccharides; D009570:Nitriles; D011725:Pyridines; D012333:RNA, Messenger; C113580:U 0126; C432165:pyrazolanthrone; D006632:Histamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006640:Histidine Decarboxylase; C093642:SB 203580