title: Involvement of histamine receptors in SAPK/JNK phosphorylation.
abstract: Histamine is a mediator of inflammation in allergic disease and asthma. Stress activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) are involved in asthma. This study examined the role of histamine receptors on the phosphorylation of SAPK/JNK in splenocytes. C57BL/6 mice splenocytes were treated with histamine (10⁻⁴ M to 10⁻¹¹ M), and its selective receptor agonists, phorbol 12 myristate 13-acetate (PMA) was used as a positive control, and phosphorylation of SAPK/JNK was determined. Histamine (10⁻⁴ M-10⁻⁸ M) inhibited phosphorylation of SAPK/JNK. H1R agonist betahistine (10⁻⁵ M) decreased SAPK/JNK phosphorylation and H2R agonist amthamine (10⁻⁵ M) did not show any significant effect. However, H3R agonist methimepip (10⁻⁶ M) and H4R agonist 4-methyl histamine (10⁻⁶ M), increased SAPK/JNK phosphorylation. We used TNFα knockout mice to determine if histamine regulated SAPK/JNK phosphorylation via TNFα. While the effects of histamine and H1 agonists were similar to that of wild type mice in inhibiting the phosphorylation of SAPK/JNK, the effects of H3 and H4 agonists differed in TNFα knockout mice splenocytes. Activation of H3 receptors decreased SAPK/JNK phosphorylation in TNFα knockout mice, as opposed to an increase in wild type mice, whereas H4 agonist did not show any significant effect on the phosphorylation of SAPK/JNK. This data showed that histamine acting through H4 receptors caused the phosphorylation of SAPK/JNK via TNFα. The role of H4 receptors in pro-inflammatory response is intriguing.
authors.affiliation: Department of Pharmaceutical Sciences, Creighton University, 2500 California Plaza, Omaha, NE 68178, 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; D001621:Betahistine / Q000494:pharmacology; D005260:Female; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D017442:Histamine Agonists; D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; D008761:Methylhistamines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C076207:amthamine; C025566:4-methylhistamine; D006632:Histamine; D013755:Tetradecanoylphorbol Acetate; D001621:Betahistine