Anti-HRH2 monoclonal antibody Made to order

Histamine functions as one of the major mediators in allergic diseases such as rhinitis, asthma, urticaria, and anaphylaxis when released from mast cells and basophils after cross-linking surface-bound IgE by allergen, The effects of histamine are mediated through three types of receptors, the H1 receptor (HRH1), H2 receptor (HRH2) and H3 receptor (Hill 1990). HRH1 mediates the proinflammatory actions of histamine in the cytokine release and adhesion process (Bachert 1998; Banu and Watanabe 1999), while HRH2 suppresses the production of the Th1-inducing cytokine interleukin-12, resulting in a shift of the Th1/Th2 balance toward Th2 dominance (van der Pouw Kraan et al. 1998). Furthermore, a linkage study identified Chromosome 3p25, where HRH1 is localized, as a candidate gene region for atopy in the Japanese population (Yokouchi et al. 1999).

Mast cells (MC) occur normally in the testis with a species-specific distribution, yet their precise role remains unclear. Testicular MC express histidine decarboxylase (HDC), the unique enzyme responsible for histamine (HA) generation. Evidence to date supports a role for HA as a local regulator of steroidogenesis via functional H 1 and H 2 receptor subtypes (HRH1 and HRH2, respectively) present in Leydig cells. Given that HA is a well-known modulator of physiological and pathological proliferation in many different cell types, we aimed in the present study to evaluate whether HA might contribute to the regulation of Leydig cell number as well as to the control of androgen production. Herein, we demonstrate, to our knowledge for the first time, that MA-10 Leydig tumor cells, but not normal immature Leydig cells (ILC), exhibit a proliferative response upon stimulation with HA that involves HRH2 activation, transient elevation of cAMP levels, and increased extracellular signal-regulated kinase (ERK) phosphorylation. Our results also reveal that MA-10 cells show significantly heightened HDC expression compared to normal ILC or whole-testicular lysate and that inhibition of HDC activity decreases MA-10 cell proliferation, suggesting a possible correlation between autocrine overproduction of HA and abnormally increased proliferation in Leydig cells. The facts that germ cells are also both source and target of HA and that multiple testicular cells are susceptible to HA action underline the importance of the present study, which we hope will serve as a first step for further research into regulation of non-MC-related HDC expression within the testis and its significance for testicular function.