H4 histamine receptors inhibit steroidogenesis and proliferation in Leydig cells

Abstract

The histamine H4 receptor (HRH4), discovered only 13 years ago, is considered a promising drug target for allergy, inflammation, autoimmune disorders and cancer, as reflected by a steadily growing number of scientific publications and patent applications. Although the presence of HRH4 has been evidenced in the testis, its specific localization or its role has not been established. Herein, we sought to identify the possible involvement of HRH4 in the regulation of Leydig cell function. We first evaluated its expression in MA-10 Leydig tumor cells and then assessed the effects of two HRH4 agonists on steroidogenesis and proliferation. We found that HRH4 is functionally expressed in MA-10 cells, and that its activation leads to the inhibition of LH/human chorionic gonadotropin-induced cAMP production and StAR protein expression. Furthermore, we observed decreased cell proliferation after a 24-h HRH4 agonist treatment. We then detected for the sites of HRH4 expression in the normal rat testis, and detected HRH4 immunostaining in the Leydig cells of rats aged 7-240 days, while 21-day-old rats also presented HRH4 expression in male gametes. Finally, we evaluated the effect of HRH4 activation on the proliferation of normal progenitor and immature rat Leydig cell culture, and both proved to be susceptible to the anti-proliferative effect of HRH4 agonists. Given the importance of histamine (2-(1H-imidazol-4-yl)ethanamine) in human (patho)physiology, continued efforts are directed at elucidating the emerging properties of HRH4 and its ligands. This study reveals new sites of HRH4 expression, and should be considered in the design of selective HRH4 agonists for therapeutic purposes.

Heme oxygenase-1 arrests Leydig cells functions and impairs their regulation by histamine

“…HA dual concentration-dependent effect on steroidogenesis has been described in MA-10 LCs and in purified rat LC. HA positively regulates steroidogenesis at low concentrations via HRH2 and negatively at high concentrations via HRH1 and HRH4 (Mondillo et al 2005, Abiuso et al 2014. Similar results were observed in R2C LCs (Abiuso et al 2018).…”

Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications

“…Last but not least, a recent work in Leydig-cell tumors (LCT), which are rare testicular endocrine tumors shows that H4R agonist VUF8430 treatment inhibited steroidogenesis and proliferation in R2C cells and also reduced pro-angiogenic capacity both in vitro and in vivo . Furthermore, H4R immunostaining was weak in LCT but moderate/strong in normal prepubertal testes (Abiuso et al, 2014, 2018).…”

Significance of mast cells in spermatogenesis, implantation, pregnancy, and abortion: Cross talk and molecular mechanisms

“…Investigation of H1‐H4 receptors in human testis is needed to have a better understanding of such cross talk. Abiuso et al reported the expression of the H4 receptor on MA‐10 Leydig tumor cells and that H4 receptor activation inhibits the proliferation of MA‐10 cells . The biologic role of MCs in cryptorchid testes needs to be studied.…”