During mast cell degranulation, histamine is released in large quantities. Human eosinophils were found to express histamine H₄ but not H₃ receptors. The possible effects of histamine on eosinophils and the receptor mediating these effects were investigated in our studies.

Histamine (0.01–30 μM) induced a rapid and transient cell shape change in human eosinophils, but had no effects on neutrophils. The maximal shape change was at 0.3 μM histamine with EC₅₀ at 19 nM. After 60 min incubation with 1 μM histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01–1 μM) also enhanced the eosinophil shape change induced by other chemokines.

Histamine‐induced eosinophil shape change was mediated by the H₄ receptor. This effect was completely inhibited by H₄ receptor‐specific antagonist JNJ 7777120 (IC₅₀ 0.3 μM) and H₃/H₄ receptor antagonist thioperamide (IC₅₀ 1.4 μM), but not by selective H₁, H₂ or H₃ receptor antagonists. H₄ receptor agonists imetit (EC₅₀ 25 nM) and clobenpropit (EC₅₀ 72 nM) could mimic histamine effect in inducing eosinophil shape change.

Histamine (0.01–100 μM) induced upregulation of adhesion molecules CD11b/CD18 (Mac‐1) and CD54 (ICAM‐1) on eosinophils. This effect was mediated by the H₄ receptor and could be blocked by H₄ receptor antagonists JNJ 7777120 and thioperamide.

Histamine (0.01–10 μM) induced eosinophil chemotaxis with an EC₅₀ of 83 nM. This effect was mediated by the H₄ receptor and could be blocked by H₄ receptor antagonists JNJ 7777120 (IC₅₀ 86 nM) and thioperamide (IC₅₀ 519 nM). Histamine (0.5 μM) also enhanced the eosinophil shape change induced by other chemokines.

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 H₄ receptor mediates eosinophil chemotaxis, cell shape change and upregulation of adhesion molecules. The effect of H₄ 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 H₄ receptor antagonists.