In this study we also profiled the expression

In this study, we also profiled the expression of the transporters in wild-type RBL-2H3 cells, RBL-2H3 Sc98 cells, and rat peritoneal mast cells. OCT1 and PMAT were expressed at high levels in both RBL-2H3 Sc98 and RBL-2H3 cells. However, OCT2 and OCT3 were weakly or least detected in RBL-2H3 Sc98 cells. The patterns of protein expression in RBL-2H3 Sc98 cells were in parallel with the results obtained in the inhibitor experiments. OCT1 mRNA has also been detected in murine basophils, but its role in histamine uptake was not considered because [3H]-histamine was poorly transported into OCT1-transfected 293 cells (Schneider et al., 2005). Histamine uptake was suppressed by a high concentration of the OCT1 inhibitor desipramine in RBL-2H3 Sc98 cells. Therefore, OCT1 might be involved in histamine uptake at a high concentration. However, because of the low level of OCT3 expression and lack of histamine uptake suppression by corticosterone in RBL-2H3 Sc98 cells, the involvement of OCT3 in histamine uptake may be negligible in RBL-2H3 cells. These findings suggest that PMAT and OCT1 might act as histamine transporters in RBL-2H3 cells.
Acknowledgments We thank Mrs. M. Shudo, T. Kiyoi (Division of Analytical Bio-medicine, Advanced Research Support Center, Ehime University), and Ms. E. Takemasa (Department of Pharmacology, Ehime University Graduate School of Medicine) for their technical advice and support, and The Directorate General of Higher Education, The Ministry of Research, Technology and Higher Education, Republic of Indonesia, for the Doctoral Scholarship granted to Trivadila. We also thank Mitchell Arico from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Introduction Histamine is known to regulate many pathophysiological processes. As examples, histamine has been shown variously to promote allergic inflammation, to induce chloroquine phosphate secretion in the gut and to modulate neurotransmission in the central nervous system (Panula et al., 2015). These effects of histamine are mediated by the histamine H1, histamine H2 and histamine H3 receptors, respectively. Historically, the histamine H1 and histamine H2 receptors have served as targets for therapeutically useful drugs, H1 anti-histamines to treat allergic symptoms (Simons and Simons, 1994) and H2 antagonists to counter excess acid secretion (Hershcovici and Fass, 2011). Targeting the histamine H3 receptor has led to the development of selective ligands involved in modifying behavioural disorders (Schwartz, 2011). More recently, a fourth receptor, the histamine H4 receptor, has been identified (Nakamura et al., 2000, Oda et al., 2000). Particular interest in the histamine H4 receptor has developed since a body of emerging data suggests an intimate association of the receptor with diseases that have an allergic basis including atopic dermatitis and asthma (Thurmond et al., 2008) as well as certain auto-immune disorders such as arthritis and multiple sclerosis (Cowden et al., 2013, Liu, 2014, Thurmond, 2015, Kim et al., 2017). Although the histamine H1 receptor has traditionally been associated with allergic reactions, the failure of H1 anti-histamines to provide much symptomatic relief in conditions such as asthma (Simons, 1999) could suggest the participation of an additional or alternative receptor which may involve the histamine H4 receptor (Liu, 2014). Supporting this contention, studies have demonstrated that the histamine H4 receptor can activate a wide variety of pro-inflammatory cells (Thurmond et al., 2008). This has led to the development of histamine H4 receptor antagonists as potential therapeutic agents for diseases with an allergic basis (Thurmond et al., 2008, Walter et al., 2011, Liu, 2014, Thurmond, 2015). 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).