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

1 During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H-4 but not H-3 receptors. The possible effects of histamine on eosinophils and the receptor mediating these effects were investigated in our studies. 2 Histamine (0.01-30 muM) induced a rapid and transient cell shape change inhuman eosinophils, but had no effects on neutrophils. The maximal shape change was at 0.3 muM histamine with EC50 at 19 nM. After 60 min incubation with 1 muM histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01-1 muM) also enhanced the eosinophil shape change induced by other chemokines. 3 Histamine-induced eosinophil shape change was mediated by the H-4 receptor. This effect was completely inhibited by H-4 receptor-specific antagonist JNJ 7777120 (IC50 0.3 muM) and H-3/H-4 receptor antagonist thioperamide (IC50 1.4 muM), but not by selective H-1, H-2 or H-3 receptor antagonists. H-4 receptor agonists imetit (EC50 25 nm) and clobenpropit (EC50 72 nm) could mimic histamine effect in inducing eosinophil shape change. 4 Histamine (0.0 1-100 muM) induced upregulation of adhesion molecules CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on cosinophils. This effect was mediated by the H-4 receptor and could be blocked by H-4 receptor antagonists JNJ 7777120 and thioperamide. 5 Histamine (0.01-10 muM) induced eosinophil chemotaxis with an EC50 of 83 nM. This effect was mediated by the H-4 receptor and could be blocked by H-4 receptor antagonists JNJ 7777120 (IC50 86 nM) and thioperamide (IC50 519 nM). Histamine (0.5 muM) also enhanced the eosinophil shape change induced by other chemokines. 6 In conclusion, we have demonstrated a new mechanism of eosinophil recruitment driven by mast cells via the release of histamine. Using specific histamine receptor ligands, we have provided a definitive proof that the H-4 receptor mediates eosinophil chemotaxis, cell shape change and upregulation of adhesion molecules. The effect of H-4 receptor antagonists in blocking eosinophil infiltration could be valuable for the treatment of allergic diseases. The histamine-induced shape change and upregulation of adhesion molecules on eosinophils can serve as biomarkers for clinical studies of H-4 receptor antagonists.