Histamine H2 receptors mediate the inhibitory effect of histamine on human eosinophil degranulation

摘要

class="enumerated" style="list-style-type:decimal">The effect of histamine on human eosinophil degranulation and the receptor mediating such effect were studied in vitro using the complement C5a-mediated eosinophil peroxidase (EPO) release model.Following pre-treatment with 5 μg ml⁻¹ cytochalasin B(CB), C5a induced a concentration-dependent release of EPO from eosinophils isolated from healthy donors.Histamine (0.1–50 μM), but not L-histidine, inhibited concentration-dependently C5a-induced EPO release with IC50 (95% CI) of 0.6 μM (0.3–1.2 μM) and maximal inhibition of ≈60%.A similar effect was seen with the selective H2 agonists dimaprit (IC50 (95% CI)=6.9 μM (3.2–10.6 μM)) and amthamine (IC50 (95% CI)=0.4 μM (0.2–0.7 μM)). Neither the selective H1 agonist 6-(2-(4-imidazolyl)ethylamino)-N-(4-trifluoromethylphenyl) heptanecarboxamide(HTMT), nor the selective H3 agonists imetit (up to 100 μM) had any significant effect.The inhibition by histamine was reversed by cimetidine (0.1–30 μM) and other H2 antagonists, but not the H1 antagonist mepyramine (1.0–100 μM), nor the H3 antagonist thioperamide (1.0–100 μM). Cimetidine (1–30 μM) shifted to the right the dimaprit log dose-response curve, producing a pA2 value of 5.9 and Schild's plot slope of 0.98, thus confirming simple competitive antagonism.Histamine (10–100 μM) increased intracellular level of adenosine 3′,5′-cyclic monophosphate, which was completely abolished by cimetidine (30 μM), but not mepyramine or thioperamide. The cyclic AMP analogue – dibutyryl cyclic AMP – also inhibited degranulation (IC50 ∼300 μM). The cyclic AMP phosphodiesterase(PDE) IV inhibitor rolipram (10 μM) synergistically enhanced the inhibition of EPO release by histamine.These results suggest that histamine, via stimulation of H2 receptors and a consequent elevation of intracellular levels of cyclic AMP, inhibits human eosinophil degranulation.