Critical Role of Histamine H4 Receptor in Leukotriene B4 Production and Mast Cell-Dependent Neutrophil Recruitment Induced by Zymosan in Vivo

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 307; no. 3; p. 1072
• Main Authors: Takeshita, Keisuke, Sakai, Katsuya, Bacon, Kevin B, Gantner, Florian
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.12.2003
• Subjects: Animals; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Carrageenan; Cimetidine - pharmacology; Cytokines - metabolism; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Histamine Antagonists - pharmacology; Histamine H1 Antagonists - pharmacology; Histamine H2 Antagonists - pharmacology; Histamine Release - drug effects; Leukotriene B4 - biosynthesis; Mast Cells - drug effects; Mast Cells - metabolism; Mice; Mice, Inbred BALB C; Neutrophil Infiltration - drug effects; Piperidines - pharmacology; Pleurisy - chemically induced; Pleurisy - pathology; Pyrilamine - pharmacology; Receptors, G-Protein-Coupled; Receptors, Histamine - drug effects; Receptors, Histamine - physiology; Receptors, Histamine H3 - drug effects; Receptors, Histamine H3 - physiology; Receptors, Histamine H4; Zymosan
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.057489

The recently identified histamine receptor, H 4 , was shown to be primarily expressed on leukocytes and has been implicated in the activation of lymphocytes, eosinophils, and mast cells in vitro. Its function in vivo, however, has not yet been characterized. We present evidence for a critical role of H 4 receptor in the mast cell-dependent recruitment of neutrophils. Mice injected with zymosan into the pleural cavity developed massive neutrophilia within hours after challenge. Neutrophilia was dose-dependently reduced when mice were pretreated with thioperamide, a known H 3/4 receptor antagonist, whereas H 1 and H 2 receptor antagonists lacked efficacy. Similarly, a 70 to 80% reduction in neutrophils in the pleural cavity compared with wild-type animals was noted in mice lacking mast cells (W/W v mice); mice deficient in MyD88 (MyD88 –/– ); a critical component of the signaling cascade of the major receptor for zymosan, toll-like receptor 2 (TLR2); or in mice pretreated with a functionally antagonistic anti-TLR2 antibody. The residual 20% neutrophil infiltration seen in mast cell-deficient and MyD88 –/– mice was not further reduced by thioperamide. Neutrophilia was completely restored by transferring wild-type bone marrow-derived mast cells into MyD88 –/– or W/W v mice. Interestingly, when neutrophilia was evoked by carrageenan injection, mast cell depletion and thioperamide had no effect. Various inflammatory mediators were detectable in the pleural cavity of zymosan-challenged mice. Upon pretreatment with thioperamide, reduced levels of the neutrophil chemattractant leukotriene B 4 were observed, providing a mechanistic explanation for the prevention of neutrophilia by H 4 receptor antagonism.