title: Regulation of ERK2 phosphorylation by histamine in splenocytes.
abstract: Histamine is implicated in allergic disease and asthma and ERK1/2 is involved in allergic inflammation including Th2 differentiation and proliferation. This study was designed to study the effects of histamine on ERK1/2 phosphorylation in splenocytes. C57/BL6 splenocytes were treated with different concentrations of histamine (10(-4) to 10(-11) M). Histamine (10(-4) M) increased ERK2 phosphorylation. There was, however, no significant effect seen at other concentrations (10(-11) to 10(-6) M). Surprisingly, H1 receptor agonist β-histine (10(-5) M), H2 agonist amthamine (10(-5) M), H3 agonist methimepip (10(-6) M), and H4 agonist 4-methyl histamine (10(-6) M), all increased ERK2 phosphorylation. H1R antagonist pyrilamine (10(-6) M), H2R antagonist ranitidine (10(-5) M), H3/H4R antagonist thioperamide (10(-6) M), and H3R antagonist clobenpropit (10(-5) M) inhibited histamine-mediated ERK2 phosphorylation suggesting that all four histamine receptor subtypes played some role in this phosphorylation. Because tumor necrosis factor-α (TNF-α) causes phosphorylation of ERK1/2, we investigated whether histamine acted via secretion of TNF-α to affect ERK1/2 phosphorylation. As a consequence, TNF-α knockout mice were used and we found that there was inhibition of ERK1 and ERK2 phosphorylation by H2, H3, and H4 agonists. This was in contrast to the wild-type splenocytes where histamine augmented the phosphorylation of ERK2 via H2, H3, and H4 receptors. In TNF-α knockout mice histamine did not affect the phosphorylation of ERK2 via H1 receptors. The results suggested that histamine indirectly caused the ERK2 phosphorylation via its effects on the secretion of TNF-α and these effects were mediated via H1, H2, H3, and H4 receptors.
authors.affiliation: Department of Pharmaceutical Sciences, Creighton University, Omaha, Nebraska, USA.
authors.forename: Radhika D
authors.initials: RD
authors.lastname: Dandekar
authors.forename: Manzoor M
authors.initials: MM
authors.lastname: Khan
mesh_terms: D000818:Animals; D005260:Female; D006632:Histamine / Q000494:pharmacology / Q000502:physiology*; D017442:Histamine Agonists / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D013154:Spleen / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency
chemical_list: D017442:Histamine Agonists; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3