title: Proinflammatory role of the histamine H4 receptor in dextrane sodium sulfate-induced acute colitis.
abstract: Millions of people worldwide are suffering from inflammatory bowel disease (IBD), which severely affects patients' life qualities and even life expectancies. The cause of the ailment is unknown and a profound understanding of the underlying pathogenetic mechanisms is still lacking. The biogenic amine histamine is one of several inflammatory mediators, to which a pathogenetic role in IBD has been attributed. Out of the four known histamine receptors, the histamine H4 receptor (H4R) has been demonstrated to act proinflammatory in experimental models of several inflammatory diseases. In order to evaluate a potential involvement of H4R in IBD we investigated the effect of genetic or pharmacological blockade of H4R-signaling in the model of dextran sodium sulfate (DSS)-induced colitis in mice. We analysed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colons and systemic or local cytokine concentrations. Both genetic deficiency and pharmacological blockade of H4R with the selective antagonist JNJ7777120 improved clinical and histological signs of colitis and dampened the inflammatory cytokine response. Our results indicate a proinflammatory role of histamine via H4R in IBD, thus extending the current pathophysiological understanding of IBD and demonstrating the therapeutic potential of selective H4R-antagonists for patients suffering from IBD.
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany. Electronic address: schirmer.bastian@mh-hannover.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schirmer
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rezniczek
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Neumann
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism*; D000074040:Receptors, Histamine H4
chemical_list: D016207:Cytokines; C498829:Hrh4 protein, mouse; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D016264:Dextran Sulfate
keywords: Cytokines; Experimental colitis; Histamine; Histamine H(4) receptor; Inflammatory bowel diseases