Cysteinyl leukotrienes mediate histamine hypersensitivity ex vivo by increasing histamine receptor numbers

Abstract

Background: Hyperresponsiveness to histamine is a key feature of a variety of pathological conditions, including bronchial asthma, food allergy, colitis ulcerosa, and topical allergic disorders. Cells isolated from hyperresponsive individuals do not display exaggerated histamine responses ex vivo and thus the molecular mechanisms underlying histamine responsiveness remain obscure. Importantly, several in vivo observations implicate cysteinyl leukotrienes as possible mediators of increased histamine responses. We decided to investigate whether cysteinyl leukotrienes enhance the cellular reaction to histamine in cell types involved in pathological and immunological histamine hyperresponsiveness, as this might provide an in vitro system for studying histamine responsiveness and could shed light on the underlying molecular mechanisms. Materials and Methods: Histamine responsiveness was determined by measuring histamine-induced prostaglandin E2 production. Scatchard analysis was performed to determine the number of histamine H1 receptors. Mouse macrophages, primary isolated human peripheral blood monocytes, and human umbilical smooth muscle cells were investigated before and after cysteinyl leukotriene stimulation. Results: In all three cell types tested, cysteinyl leukotrienes instantaneously enhanced histamine-induced prostaglandin E2 production. This increase in prostaglandin E2 production coincided with the immediate and transient appearance of additional H1 receptors on the plasma membrane. Conclusions: Cysteinyl leukotrienes prime histamine responses by recruiting additional histamine receptors in immunologically relevant cell types in vitro.