Histamine induces cytoskeletal changes in human eosinophils via the H 4 receptor

Histamine (0.004–2 μ M ) induced a concentration‐dependent shape change of human eosinophils, but not of neutrophils or basophils, detected as an increase in forward scatter (FSC) in the gated autofluorescence/forward scatter (GAFS) assay. The histamine‐induced eosinophil shape change was completely abolished by thioperamide (10 μ M ), an H 3 /H 4 receptor antagonist, but was not inhibited by pyrilamine or cimetidine (10 μ M ), H 1 and H 2 receptor antagonists, respectively. The H 4 receptor agonists, clobenpropit and clozapine (0.004–2 μ M ), which are also H 3 receptor antagonists, both induced eosinophil shape change, which was inhibited by thioperamide (10 μ M ). The H 3 /H 4 receptor agonists, imetit, R ‐ α ‐methyl histamine and N ‐ α ‐methyl histamine (0.004–2 μ M ) also induced eosinophil shape change. Histamine induced actin polymerisation (0.015–10 μ M ), intracellular calcium mobilisation (10–100 μ M ) and a significant upregulation of expression of the cell adhesion molecule CD11b (0.004–10 μ M ) in eosinophils, all of which were inhibited by thioperamide (10–100 μ M ). In addition, the H 4 receptor agonist/H 3 receptor antagonist clozapine (20 μ M ) stimulated a rise in intracellular calcium in eosinophils. Activation of H 4 receptors by histamine (1 μ M ) primed eosinophils for increased chemotactic responses to eotaxin, but histamine (0.1–10 μ M ) did not directly induce chemotaxis of eosinophils. Pertussis toxin (1 μ g ml −1 ) inhibited shape change and actin polymerisation responses induced by histamine showing that these effects are mediated by coupling to a G α i/o G‐protein. This study demonstrates that human eosinophils express functional H 4 receptors and may provide a novel target for allergic disease therapy.British Journal of Pharmacology (2003) 140 , 1117–1127. doi: 10.1038/sj.bjp.0705530