Progestogens cause immunosuppression of stimulated carp (Cyprinus carpio L.) leukocytes in vitro.

ABSTRACT

The involvement of steroid hormones in direct and indirect regulation and modulation of immune responses is well recognized in mammals. Here, we demonstrate that progestogens are capable of influencing the innate immunity in fish as well. Therefore, we confirmed the known immunosuppressive effects of natural progesterone (P4), and compared them to influences of 17alpha,20beta-dihydroxy progesterone (DHP4) and the synthetic progestins, medroxyprogesterone acetate (MPA) and levonorgestrel (LEV), on NO release by in vitro-stimulated carp leukocytes derived from both, head and trunk kidney, respectively. DHP4 known as the main maturation-inducing steroid in many teleosts potently inhibited the NO release by carp leukocytes. The synthetic progestin MPA, which may also be environmentally relevant due to its world-wide use in hormonal contraception, significantly decreased NO formation by head and trunk kidney cells. In contrast, LEV showed no significant influence on NO release by head and trunk kidney leukocytes. The observed immunosuppressive actions of progestogens on NO production were compared to the known impairment by natural and synthetic glucocorticoids. Determining the potential impact of progestogens on mRNA expression of iNOS by means of semi-quantitative reverse transcription polymerase chain reactions (RT-PCR) revealed downregulation of proinflammatory type I immune response characteristics at high concentrations. These findings demonstrate for the first time that similar to the known effects of natural progesterone synthetic progestogens are also able to influence immune signaling cascades in fish, and provide evidence that these steroids are capable of influencing mRNA expression of iNOS. The induction of a regulatory type II immune response by progestogens is a striking example of interference of female steroid-mediated events with the piscine immune system. Furthermore, the identification of a partial sequence of a membrane-associated progestogen receptor (mPR) in carp leukocytes by RT-PCR indicates a specific mechanism underlying the observed effects of progestogens on these immune cells.