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: Bastian Schirmer, Thomas Rezniczek, Roland Seifert, Detlef Neumann
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 98 Issue 1 Pg. 102-9 (Nov 01 2015) ISSN: 1873-2968 [Electronic] England
• PMID: 26365468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Hrh4 protein, mouse
• Indoles
• Piperazines
• Receptors, G-Protein-Coupled
• Receptors, Histamine
• Receptors, Histamine H4
• 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
• Dextran Sulfate

Topics

• Animals
• Colitis (chemically induced, metabolism)
• Cytokines (genetics, metabolism)
• Dextran Sulfate (toxicity)
• Gene Expression Regulation (physiology)
• Indoles (pharmacology)
• Mice
• Mice, Knockout
• Piperazines (pharmacology)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Receptors, Histamine (genetics, metabolism)
• Receptors, Histamine H4