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The diverse effects of histamine are mediated by discrete histamine receptors. The principal repository of histamine in the body is the mast cell. However, the effects of histamine on mast cells, especially those of human origin, have not been fully elucidated. In this study, the expression of histamine receptors in human lung mast cells was evaluated. Moreover, the effects of histamine receptor engagement on both mediator release and chemotaxis were investigated. Mast cells were isolated and purified from human lung tissue. Histamine receptor expression was determined by RT-PCR and q-PCR. Both methods for the detection of histamine receptors were in accordance and human lung mast cells expressed mRNA for histamine H4 and histamine H1 receptors, variably expressed histamine H2 receptor but did not express histamine H3 receptor. The effects of selective histamine receptor agonists on the release of both pre-formed (histamine) and newly-synthesised (cysteinyl-leukotriene, prostaglandin D2) mediators were investigated. None of the agonists tested had any direct effects on mediator release. None of the agonists modulated release stimulated by anti-IgE. Further studies showed that histamine induced migration of mast cells. Chemotaxis appeared to be mediated by the histamine H4 receptor since JNJ28610244 (H4 agonist) was chemotactic for mast cells whereas 2-(2-pyridyl) ethylamine (H1 agonist) was not. Furthermore, the selective histamine H4 receptor antagonist, JNJ7777120, effectively reversed the chemotaxis of mast cells induced by JNJ28610244. Overall, these experiments identify the histamine H4 receptor as chemotactic for human lung mast cells. This mechanism might influence mast cell accumulation in the lung.