Short communicationHistamine H4 receptors regulate ACTH release in AtT-20 cells
Introduction
The histamine H4 receptor is a relatively newly discovered member of histamine receptors. It has a distinct expression profile on immune cells, including mast cells, eosinophils, dendritic cells, and T cells, and appears to play a role in multiple functions of these cells, such as, activation, migration, cytokine and chemokine production (Zhang et al., 2007, de Esch et al., 2005, Dunford et al., 2006). Earlier researchers have identified histamine H3 receptors in rat and guinea-pig pituitary glands and in the mouse pituitary tumor cell line, AtT-20. Histamine H3 receptor agonists N-α-methylhistamine and R-α-methylhistamine are reported to bind to AtT-20 cell membranes, as well as to stimulate adrenocorticotropic hormone (ACTH) release from the cells. The effect was blocked by histamine H3, but not H1 or H2 receptor antagonists. Therefore, it was concluded that high affinity histamine H3 receptor regulated ACTH release from that cells (Clark et al., 1992, West et al., 1994).
However, it has been reported recently that histamine H3 receptor agonist, N-α-methylhistamine bound specifically to histamine H4 receptor with high affinity, while another H3 agonist, R-α-methylhistamine, and the H3 antagonist, thioperamide, competed with this binding. N-α-methylhistamine and R-α-methylhistamine also produced a reduction in forskolin-induced cAMP accumulation in histamine H4 receptor-expressing cells (Nakamura et al., 2000). Moreover, functional studies demonstrate that histamine H3 receptor either in central nervous system or in peripheral tissues mainly exerts “inhibitory effects”, such as negative control on neurotransmitter release or gastric acid secretion (van der Werf and Timmerman, 1989, Levi and Smith, 2000, Coruzzi et al., 2001). Oppositely, the activation of histamine H4 receptor has been shown to have “excitatory effects”, such as chemotaxis and mediator release in various types of immune cells including mast cells, monocytes, eosinophils, dendritic cells and T cells (Hofstra et al., 2003, Ling et al., 2004, Zhang et al., 2006, Damaj et al., 2007). All these results imply that histamine receptor mediated ACTH secretion from AtT-20 may not be related to the actions H3 subtype of histamine receptors. Here we provide definitive proof that histamine H4 receptors are expressed in AtT-20 cells and involved in modulation of ACTH release from the cells.
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Materials and methods
The mouse pituitary tumor AtT-20 cells were obtained from American Type Culture Collection (Bethesda, MD, USA). The cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 U/ml streptomycin, 100 U/ml penicillin at 37 °C in a 5% CO2 atmosphere. Culture medium was changed every 3 days. Total RNA was isolated from AtT-20 cells and mouse spleens with Trizol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacture's instructions, and the
Histamine H4 receptor expression in AtT-20 cells
To determine whether histamine H4 receptor existed in AtT-20 cells, we performed RT-PCR to examine the gene expression of histamine H4 receptor. RNA from mouse spleen was chosen as a positive control, as histamine H4 receptor are dominantly expressed in mouse spleen. The segment of histamine H4 receptor gene was detected in both AtT-20 cells and mouse spleen (Fig. 1A). The primer sequences used in the present study specifically bound to corresponding sequence of mouse histamine H4 receptor cDNA
Discussion
The recently identified histamine H4 receptor is localized in the peripheral blood leukocytes, spleen, thymus, small intestine, colon, bone marrow and synovial cells. The tissue distribution of the histamine H4 receptor and known physiological function of histamine lead us to speculate about its function as an immune modulator and a possible link to the pathology of allergy and asthma (Zhang et al., 2006, Dunford et al., 2006, de Esch et al., 2005). Based on homology analysis, the amino acid
Acknowledgments
The authors wish to thank Dr. Robin L Thurmond, Johnson & Johnson Pharmaceutical Research and Development, for the kind gift of JNJ7777120.
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