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

Abstract

1 The e ect of histamine on human eosinophil degranulation and the receptor mediating such e ect were studied in vitro using the complement C5a-mediated eosinophil peroxidase (EPO) release model. 2 Following pre-treatment with 5 mg ml 71 cytochalasin B(CB), C5a induced a concentrationdependent release of EPO from eosinophils isolated from healthy donors. 3 Histamine (0.1 ± 50 mM), but not L-histidine, inhibited concentration-dependently C5a-induced EPO release with IC 50 (95% CI) of 0.6 mM (0.3 ± 1.2 mM) and maximal inhibition of &60%. 4 A similar e ect was seen with the selective H 2 agonists dimaprit (IC 50 (95% CI)=6.9 mM (3.2 ± 10.6 mM)) and amthamine (IC 50 (95% CI)=0.4 mM (0.2 ± 0.7 mM)). Neither the selective H 1 agonist 6-(2-(4-imidazolyl)ethylamino)-N-(4-tri¯uoromethylphenyl) heptanecarboxamide(HTMT), nor the selective H 3 agonists imetit (up to 100 mM) had any signi®cant e ect. 5 The inhibition by histamine was reversed by cimetidine (0.1 ± 30 mM) and other H 2 antagonists, but not the H 1 antagonist mepyramine (1.0 ± 100 mM), nor the H 3 antagonist thioperamide (1.0 ± 100 mM). Cimetidine (1 ± 30 mM) shifted to the right the dimaprit log dose-response curve, producing a pA 2 value of 5.9 and Schild's plot slope of 0.98, thus con®rming simple competitive antagonism. 6 Histamine (10 ± 100 mM) increased intracellular level of adenosine 3',5'-cyclic monophosphate, which was completely abolished by cimetidine (30 mM), but not mepyramine or thioperamide. The cyclic AMP analogue ± dibutyryl cyclic AMP ± also inhibited degranulation (IC 50 *300 mM). The cyclic AMP phosphodiesterase(PDE) IV inhibitor rolipram (10 mM) synergistically enhanced the inhibition of EPO release by histamine. 7 These results suggest that histamine, via stimulation of H 2 receptors and a consequent elevation of intracellular levels of cyclic AMP, inhibits human eosinophil degranulation.

Histamine Receptors and Antihistamines: From Discovery to Clinical Applications

“…In 1973, Lichtenstein and Gillespie [33] reported that H 2 R are functionally present on human basophils. Subsequently, H 2 R were found on rodent mast cells [34] , human eosinophils [35,36] and human neutrophils [37] .…”

Current Knowledge and Perspectives on Histamine H1and H2Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

“…These cells are chemoattracted and migrate to the focus of infection, releasing a variety of cytotoxic enzymes, cytokines, and ROS playing a pivotal role in host defense against microbes and viruses (Pincus et al, 1982;Burde et al, 1989;Adamko et al, 2002;Rothenberg and Hogan, 2006;Soehnlein et al, 2009;Sadik et al, 2011;Reher et al, 2012b). H 2 R activation results in inhibition of granulocyte superoxide release (Gespach and Abita, 1982;Burde et al, 1989;Ezeamuzie and Philips, 2000). Although cAMP increments are related to inhibition of ROS release, substantial evidence has shown that H 2 R agonists dimaprit and impromidine are biased ligands toward ROS inhibition over cAMP production in neutrophils and eosinophils (Reher et al, 2012a).…”

Mast Cell Tryptase Activates Peripheral Blood Eosinophils to Release Granule-Associated Enzymes

“…Much less is known regarding the effects of mast cell mediators on eosinophil degranulation. The only clear evidence concerns histamine, which inhibits eosinophil degranulation through its effects on H 2 receptors [45]. Our data indicate that mast cell tryptase may be important in inducing degranulation from eosinophils accumulating in areas of mast cell activation.…”