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 H3/H4 receptor antagonist thioperamide, but not by H1 or H2 receptor antagonists. This chemotactic response is mediated by the H4 receptor, because chemotaxis toward histamine was absent in mast cells derived from H4 receptor-deficient mice but was detected in H3 receptor-deficient mast cells. In addition, Northern blot analysis showed the expression of H4 but not H3 receptors on mast cells. Activation of H4 receptors by histamine resulted in calcium mobilization from intracellular calcium stores. Both Gαi/o proteins and phospholipase C (PLC) are involved in histamine-induced calcium mobilization and chemotaxis in mast cells, because these responses were completely inhibited by pertussis toxin and PLC inhibitor 1-[6-[[17β-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 H4 receptor. This mechanism might be responsible for mast cell accumulation in allergic tissues.
Footnotes
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↵ 1 Current address: NV Organon, Molenstraat 110, P.O. Box 20, 5340 BH Oss, The Netherlands. E-mail: claudia.hofstra{at}organon.com
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.046581.
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ABBREVIATIONS: PTX, pertussis toxin; H3R-/-, H3 receptor gene knockout; H4R-/-, H4 receptor gene knockout; RT, reverse transcription; PCR, polymerase chain reaction; bp, base pair(s); Th, T helper; Tc, T-cytotoxic cells; FCS, fetal calf serum; IL, interleukin; LTB4, leukotriene B4; BSA, bovine serum albumin; PBS, phosphate-buffered saline; DNP-HSA, dinitrophenyl human serum albumin; IP3, inositol 1,4,5-triphosphate; U-73122, 1-[6-[[17β-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione; U-73343, 1-[6-[[17β-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidine-dione.
- Received November 5, 2002.
- Accepted February 25, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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