Histamine‐induced inhibition of leukotriene biosynthesis in human neutrophils: involvement of the H2 receptor and cAMP

摘要: Histamine is generally regarded as a pro-inflammatory mediator in diseases such allergy and asthma. A growing number of studies, however, suggest that this autacoid also involved the downregulation human polymorphonuclear leukocyte (PMN) functions inflammatory responses through activation Gs-coupled histamine H2 receptor. We report here inhibits thapsigargin- ligand (PAF fMLP)-induced leukotriene (LT) biosynthesis PMN dose-dependent manner. The suppressive effect on LT was abrogated by receptor antagonists cimetidine, ranitidine, tiotidine. In contrast, H1, H3, H4 used study were ineffective counteracting inhibitory activated PMN. The inhibition characterized decreased arachidonic acid release 5-lipoxygenase translocation to nuclear membrane. Incubation with cAMP-dependent protein kinase (PKA) inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide prevented biosynthesis, suggesting an important role for PKA PMN. These data provide first evidences that, similarly adenosine prostaglandin E2, potent suppressor support concept may play dual regulation inflammation. Keywords: 5-Lipoxygenase, acid, autacoid, cAMP, histamine, leukocyte, leukotriene, lipid mediator, PKA Introduction Leukotrienes (LTs) are mediators inflammation derived from oxygenation (AA) (5-LO). LTB4 chemoattractant activates leukocytes (Ford-Hutchinson et al., 1980; Palmblad 1981; Dewald & Baggiolini, 1985). Moreover, de novo has been shown rabbit blood transmigration elicited wide variety (Marleau 1999). The cysteinyl-LT (LTC4, D4 E4) induce bronchoconstriction (Dahlen 1980), increase vascular permeability 1981), smooth muscle cell proliferation (Cohen 1995; Rajah 1996). PMN, initiated rise intracellular calcium concentration ([Ca2+]i), followed translocations type IVA cytosolic phospholipase A2 (cPLA2) 5-LO envelope (Woods 1993; Pouliot 1996), where likely occurs. cAMP-elevating agents have reported be inhibitors product generation. Adenosine A2A agonist CGS-21680 indeed inhibit generation whole (Krump 1996) 1997; Krump Borgeat, other cAMP-elevating, namely (PG) β-adrenergic isoproterenol, IV phosphodiesterase, (Ham 1983; Schudt 1991; Fonteh Dennis Riendeau, 1999; Flamand 2000). Although cAMP-mediated clearly implicates AA (Fonteh 2000) (Flamand 2002), molecular mechanisms these events remain poorly understood. Histamine well-known associated biological effects implicate different subtypes; actions including vasodilatation increased mainly mediated H1 (H1R) occupancy. symptom attenuation allergic achieved using H1R antagonists. Other studies histamines participate adhesion endothelial wall stimulation molecule expression cells H1R-dependent manner (Miki 1996; Saito Burns Interestingly, opposite functional responses. Indeed, lysosomial enzyme release, respiratory burst, adhesion, chemotaxis, influx agonist-stimulated (Busse Sosman, 1976; Busse Radermecker Maldague, Seligmann Burde 1989; Zimmerman Millard, Francis Hirasawa Bury Radermecker, 1992; Leino 1993). All consequence H2R activation, which causes elevation cAMP concentrations ([cAMP]i) (Gespach Abita, 1982). Since possesses H2R, we investigated putative impact ability generate LTB4. We vitro. observed only mimicked specific amthamine, tiotidine, but not H1R, H3R, or H4R correlated membranes. (H-89) efficiently biosynthesis.