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  • Immune modulation by steroid hormones is a rather new

    2019-07-08

    Immune modulation by steroid hormones is a rather new aspect of the research on endocrine interactions in lower vertebrates (Harris and Bird, 2000). In the classical view, steroids exert their effects by binding to specific intracellular receptors that function as ligand-activated transcriptional regulators. Congruently, different types of activators and repressors that selectively bind their cognate sites in the regulatory elements of NO-responsive genes are matched and activate or repress transcription in a coordinated fashion. One mechanism by which glucocorticoids downregulate the immune response is related to their capacity to block induction of cytokine genes, such as IL-1, IL-2, IL-6, TNF α and INF γ as well as to reduce the capacity of these cytokines to modulate a variety of cellular effector functions (Weyts et al., 1999). Nevertheless, steroid actions are not only mediated via specific nuclear receptors but also by G protein-coupled membrane-bound receptors which signal via secondary messengers. Thereby, rapid non-genomic effects of steroid hormones can mediate fast reactions (Ehring et al., 1998, Falkenstein et al., 2000). Accordingly, it has been reported for human myometrial cells that two mPR isoforms, mPR α and mPR β, are present which probably signal via specific G proteins (Karteris et al., 2006). Similarly, mPR β also participates in oocyte maturation in Xenopus laevis suggesting the involvement of several G protein-coupled receptors in initiation and resumption of meiosis in Fomepizole (Ben-Yehoshua et al., 2007). In cyprinid fish, description of membrane-bound progestogen receptors (mPR) is restricted to goldfish and zebrafish ovaries (Hanna et al., 2006), and piscine cytosolic progestogen receptors have been found in eel and zebrafish ovaries (Todo et al., 2000, Bertrand et al., 2007). Accordingly, two isoforms, mPR α and mPR β from zebrafish, have been shown to be specifically activated by DHP4 (Hanna et al., 2006), and progestin binding resulted in rapid activation of mitogen-activated protein kinases (MAPK). Recently, an additional γ isoform of mPR has been identified in fish (Kazeto et al., 2005a), and at least six mPR-related sequences were retrieved from the fugu fish genome database, including the isoforms α, β and γ. Interestingly, an extra-gonadal function has been suggested for the mPR α due to its tissue distribution. However, the precise molecular structure of mPRs and their mechanisms of action remain unexplained (Losel et al., 2003, Norman et al., 2004). Therefore, mPRs have been grouped into a novel family of membrane-bound receptors (Tang et al., 2005). In some fish a rise in plasma progesterone (P4) levels and changes of mPR abundance in gonads were reported to be associated with oocyte maturation and ovulation (Kagawa et al., 1981, Kazeto et al., 2005b) and sperm mobility is also regulated by non-genomic progesterone actions in fish and mammals (Blackmore, 1993, Thomas et al., 1998). In contrast to mammals, in which P4 mediates the most progestational reactions, 17α,20β-dihydroxy progesterone (DHP4) is an important progestogen in fish (Todo et al., 2000, Miura et al., 2007). In our study, we intended to increase the knowledge about immunomodulatory effects of progestogens using also synthetic compounds. The world-wide use of synthetic progestins like medroxyprogesterone acetate (MPA) and levonorgestrel (LEV) in hormonal contraception, hormone replacement therapy and cancer treatment (Pogmore and Jequier, 1979, Brache et al., 2001, Boostanfar et al., 2003) might lead to the occurrence of progestins at environmentally relevant concentrations in surface waters. Congruently, LEV concentrations ranging between 0.004 nM and 0.02 nM have been reported for environmental water samples (Pu et al., 2008). Moreover, LEV levels of up to 0.54 nM have been found in raw sewage, whereas the effluent from a sewage treatment plant showed concentrations of LEV which were five times lower compared to untreated sewage (Viglino et al., 2008). However, MPA has been found at much less concentrations in several environmental samples (Kolodziej et al., 2003, Chang et al., 2008, Viglino et al., 2008). Nevertheless, anthropogenic input of substances to the aquatic environment and their conversion to P4 by microbes (Jenkins et al., 2003), can also lead to progestogen accumulation in aquatic ecosystems and could impair the natural regulation of immunity in fish as well.