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

1. Histamine is generally regarded as a pro-inflammatory mediator in diseases such as allergy and asthma. A growing number of studies, however, suggest that this autacoid is also involved in the downregulation of human polymorphonuclear leukocyte (PMN) functions and inflammatory responses through activation of the Gs-coupled histamine H-2 receptor. 2 We report here that histamine inhibits thapsigargin- and ligand (PAF and fMLP)-induced leukotriene (LT) biosynthesis in human PMN in a dose-dependent manner. 3 The suppressive effect of histamine on LT biosynthesis was abrogated by the histamine H-2 receptor antagonists cimetidine, ranitidine, and tiotidine. In contrast, the histamine H-1, H-3, and H-4 receptor antagonists used in this study were ineffective in counteracting the inhibitory effect of histamine on the biosynthesis of LT in activated human PMN. 4 The inhibition of LT biosynthesis by histamine was characterized by decreased arachidonic acid release and 5-lipoxygenase translocation to the nuclear membrane. 5 Incubation of PMN with the cAMP-dependent protein kinase (PKA) inhibitor N-[2-(P-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide prevented the inhibitory effect of histamine on LT biosynthesis, suggesting an important role for PKA in this effect of histamine on LT biosynthesis in PMN. 6 These data provide the First evidences that, similarly to adenosine and prostaglandin E-2, histamine is a potent suppressor of LT biosynthesis, and support the concept that histamine may play a dual role in the regulation of inflammation.