Histamine H₄Receptor Mediates Chemotaxis and Calcium Mobilization of Mast Cells

Abstract

The diverse physiological functions of histamine are mediated through distinct histamine receptors. Mast cells are major producers of histamine, yet effects of histamine on mast cells are currently unclear. The present study shows that histamine induces chemotaxis of mouse mast cells, without affecting mast cell degranulation. Mast cell chemotaxis toward histamine could be blocked by the dual H 3 /H 4 receptor antagonist thioperamide, but not by H 1 or H 2 receptor antagonists. This chemotactic response is mediated by the H 4 receptor, because chemotaxis toward histamine was absent in mast cells derived from H 4 receptor-deficient mice but was detected in H 3 receptor-deficient mast cells. In addition, Northern blot analysis showed the expression of H 4 but not H 3 receptors on mast cells. Activation of H 4 receptors by histamine resulted in calcium mobilization from intracellular calcium stores. Both G␣i/o proteins and phospholipase C (PLC) are involved in histamineinduced calcium mobilization and chemotaxis in mast cells, because these responses were completely inhibited by pertussis toxin and PLC inhibitor 1- [6-[[17␤-3-methoxyestra-1,3,5 (10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122). In summary, histamine was shown to mediate signaling and chemotaxis of mast cells via the H 4 receptor. This mechanism might be responsible for mast cell accumulation in allergic tissues.

Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation

“…However, the leukocyte cell types expressing H 4 receptor are still controversial. We and other groups have previously shown that the H 4 receptor is expressed in mast cells, basophils and eosinophils, and this cell type specificity is conserved in humans and mice (Oda et al, 2000;Liu et al, 2001a;Morse et al, 2001;Hofstra et al, 2003).…”

“…Since the discovery of the new histamine H 4 receptor, accumulated information in the literature suggests that H 4 receptor expression is restricted to cells of the hematopoietic (Oda et al, 2000;Liu et al, 2001a;Morse et al, 2001;Zhu et al, 2001;Hofstra et al, 2003). However, the leukocyte cell types expressing H 4 receptor are still controversial.…”

“…However, the physiological role of H 4 receptor is still unclear. We recently reported that the H 4 receptor mediates mast cell chemotaxis (Hofstra et al, 2003). The chemotactic effects of histamine on eosinophils have also been suggested in early studies (Clark et al, 1975).…”

Histamine H4 antagonism: a therapy for chronic allergy?

“…In addition, JNJ7777120 blocked chemotaxis as well as the histamine-induced upregulation of the adhesion molecules CD11b and CD54. The reports by Buckland et al (2003), and Ling et al (2004, this issue) follow a recent study which showed that H 4 was responsible for chemotaxis of mast cells (Hofstra et al, 2003). To illustrate this, these authors performed elegant chemotaxis experiments on mast cells *Author for correspondence; E-mail: bruce_daugherty@merck.com British Journal of Pharmacology (2004) (Figure 1).…”

“…Clearly, novel small molecule H 4 receptor antagonists such as JNJ7777120 (Jablonowski et al, 2003;Ling et al, 2004, this issue) will be evaluated in animals, and these studies, along with those with the available H 4 -receptor-deficient mouse (Hofstra et al, 2003), will elucidate the role of H 4 in animal models of allergic inflammation. It is highly likely that JNJ7777120 and/or its analogs, given appropriate pharmacokinetic/pharmacodynamic profiles and bioavailability, will soon be tested in the clinic, to treat chronic inflammatory diseases in humans, such as allergic respiratory, gastrointestinal, and skin diseases, where eosinophils and mast cells are thought to play prominent roles in disease pathogenesis (Rothenberg, 1998).…”