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 microm) 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 microm histamine with EC(50) at 19 nm. After 60 min incubation with 1 microm histamine, eosinophils were desensitized and were refractory to shape change response upon histamine restimulation. Histamine (0.01-1 microm) 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 (IC(50) 0.3 microm) and H(3)/H(4) receptor antagonist thioperamide (IC(50) 1.4 microm), but not by selective H(1), H(2) or H(3) receptor antagonists. H(4) receptor agonists imetit (EC(50) 25 nm) and clobenpropit (EC(50) 72 nm) could mimic histamine effect in inducing eosinophil shape change. 4. Histamine (0.01-100 microm) induced upregulation of adhesion molecules CD11b/CD18 (Mac-1) and CD54 (ICAM-1) on eosinophils. 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 microm) induced eosinophil chemotaxis with an EC(50) of 83 nm. This effect was mediated by the H(4) receptor and could be blocked by H(4) receptor antagonists JNJ 7777120 (IC(50) 86 nm) and thioperamide (IC(50) 519 nm). Histamine (0.5 microm) 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.
Ling
Ping
P
Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
Ngo
Karen
K
Nguyen
Steven
S
Thurmond
Robin L
RL
Edwards
James P
JP
Karlsson
Lars
L
Fung-Leung
Wai-Ping
WP
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D011968:Receptors, Histamine / Q000502:physiology*; D000074040:Receptors, Histamine H4; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D015815:Cell Adhesion Molecules; C418607:HRH4 protein, human; D006633:Histamine Antagonists; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D006632:Histamine