The mast cell has long been recognized as central to

The mast cell has long been recognized as central to the mediation of allergic responses not least because it is the principal repository of histamine in the body. Following activation by allergens, the mast cell can release histamine as well as generate a host of additional mediators such as cysteinyl-leukotrienes (cys-LTs) and prostaglandin D2 (PGD2). These mediators act in concert to promote inflammation and, if mast cell activation occurs in the lung, these mediators can promote potent bronchoconstriction (Bingham and Austen, 2000, Bradding et al., 2006). There have been a few studies investigating the effects of histamine on mast cells but the majority of these has been on rodent and cultured mast cells (Hofstra et al., 2003, Lippert et al., 2004, Jemima et al., 2014). How representative these systems are of primary human cells is a moot point since a great deal of heterogeneity is known to exist among mast cells isolated from different species and from different sites of the same species (Pearce, 1983, Lowman et al., 1988). In addition, an added layer of complexity exists since it is known that, despite similarities in amino interleukins sequence among orthologues of rodent and human histamine receptors, functional responses to given ligands can be markedly different (Leurs et al., 2009, Lim et al., 2010). The aim of this study, therefore, was to investigate the potential regulation of human lung mast cells by histamine receptors with particular emphasis on the role that the histamine H4 receptor might play.
Materials and methods
Results
Discussion In the present study, we have assessed whether histamine receptors modulate the function of human lung mast cells. The principal finding of this paper is that the histamine H4 receptor mediates migration of human lung mast cells. Initial experiments were performed to determine the expression of histamine receptor subtypes in human lung mast cells. Our studies, using both RT-PCR and q-PCR, demonstrated that lung mast cells appear to express histamine H4 and histamine H1 receptors prominently, histamine H2 receptors more variably among preparations and are devoid of histamine H3 receptors. These statements of the relative expression levels of histamine receptor genes should be treated with caution since it is known that the efficiency of PCR amplification can be influenced by the primer pairs selected. Nonetheless, it is noteworthy that disparate methods, RT-PCR and q-PCR, showed similarity in the expression pattern of histamine receptors. A wide variety of mast cells isolated from different species, cultured mast cell lines and human basophils all appear to express histamine H4 receptors with variable expression of histamine H1 and/or histamine H2 receptors reported (Hofstra et al., 2003, Lippert et al., 2004, Jemima et al., 2014, Mommert et al., 2016). No studies so far have shown that mast cells express histamine H3 receptors. Given that expression of the histamine H3 receptor is most commonly associated with the CNS (Schwartz, 2011), this may not be an altogether unexpected finding. In further studies, the effects of receptor-selective agonists on functional responses were investigated. There was no evidence that any of the agonists selective for a particular histamine receptor were able to induce degranulation or eicosanoid generation from human lung mast cells. Moreover, there was no indication that any of the same histamine agonists could modulate IgE-dependent mediator release. These findings are at odds with studies in human mast cell lines (HMC-1 and LAD2 cells) and cord-blood derived mast cells in which 4-methylhistamine, a putative agonist at histamine H4 receptors, was able to induce both degranulation and cys-LT generation and these effects of 4-methylhistamine were reversed by the histamine H4 receptor antagonist JNJ777120 (Jemima et al., 2014). In broader agreement with the present study, H4 agonists were unable to stimulate degranulation or eicosanoid generation in mouse mast cells (Hofstra et al., 2003). These findings are in stark contrast to studies in human basophils in which a histamine H4 receptor agonist, ST-1006, inhibited cys-LT generation and other indices of basophil activation (Mommert et al., 2016). The reasons for these differences in responses among different mast cell types are not immediately apparent. However, the findings highlight the well-recognized functional heterogeneity that exists among mast cells isolated from different species and from sites within the same species (Pearce, 1983, Lowman et al., 1988).