Cytokines Influence on Steroidogenesis

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Cytokines take part in gonadal steroidogenesis (Fig. 9.2). In testis, they are physiologically produced by Sertoli cells and Leydig cells and they regulate cell proliferation as well as steroidogenesis. However, increased concentrations of cytokines may adversely influence cell function. For example, IL-1a may negatively influence expression of regulatory protein steroidogenic acute regulator (StAR) as well as its phosphorylation, thus inhibiting cholesterol translocation to inner mitochondrial membrane. In physiological conditions, IL-1 stimulates Leydig cells to secretion of progesterone and testosterone [25, 26].

The Leydig cells show mRNA expression for both IL-1a and IL-1P in in vitro conditions as a response to the lipopolysaccharides (LPSs) or exogenous IL-1 activity [27, 28]. It is suggested that IL-1 inhibits the LH-dependent synthesis of testosterone by the Leydig cells, which is caused by the decrease of hCG-dependent synthesis of cAMP, lowering of the level of P450scc enzyme [29], and inhibition of P450c17 and 3P-HSD enzymes [30]. During inflammation, the presence of both isoforms of interleukin 1 may be found, also in the interstitial fluid of the testes, where they regulate the immunological response occurring in the gonad [31, 32].

The inhibition of testosterone production can be caused also by the direct influence of IL-2 on the Leydig cells as well as indirect way through activation of TNF-a and IL-1 secreted by macrophages found in the gonad. IL-2 stimulates the hypotha-lamic-pituitary-adrenal axis resulting in the increase in the ACTH and glycocorti-costeroid levels, which in turn may have an inhibitory influence on steroidogenesis in the Leydig cells [30] .

LPSs activate macrophages and monocytes, which in turn secrete TNF-a. In physiological conditions, the presence of mRNA for TNF-a is observed in sper-matids and pachytene spermatocytes as well as in interstitial macrophages of testes [33]. In the Leydig cells, TNF-a causes inhibition of testosterone production

Hypothalamus-pituitary-testicular axis

Hypothalamus-pituitary-testicular axis

Testicular Steroidogenesis

Fig. 9.2 Influence of inflammatory mediators on Leydig cell and testosterone synthesis. Inflammatory mediators, like ROS, lipopolysaccharides (LPSs), NO, or cytokines, inhibit testosterone production in Leydig cells because of their activity against steroidogenic acute regulatory (StAR) protein, 3^-hydrosteroid dehydrogenase (3b-HSD), P450c17, or 17^-hydroxysteroid dehydrogenase

Fig. 9.2 Influence of inflammatory mediators on Leydig cell and testosterone synthesis. Inflammatory mediators, like ROS, lipopolysaccharides (LPSs), NO, or cytokines, inhibit testosterone production in Leydig cells because of their activity against steroidogenic acute regulatory (StAR) protein, 3^-hydrosteroid dehydrogenase (3b-HSD), P450c17, or 17^-hydroxysteroid dehydrogenase stimulated by AMP through a decrease of mRNA for the cytochrome P450 enzymes: splitting the cholesterol side-chain cleavage enzyme [34] and 7a-hydrox-ylase/C1720 lyase [33],

The Leydig cells secrete IFNs, which are in the first line of defense against viruses. They are the only cells of the gonad which produce both types of interferons (a and b). In high concentration, IFNa has an inhibitory influence on the testosterone production stimulated by LH in the Leydig cells through inhibition of expression of the StAR protein [35] and enzymes P450scc and P450c17.

The proteins of the TGFb family are secreted in the gonad in high concentrations by the Sertoli cells, peritubular cells, and the Leydig cells. Most often, they are found in an inactive form and activation is provoked by the activity of local proteases. In physiological conditions, TGFbs function as regulators of the Leydig and reproductive cells proliferation, the Leydig cells steroidogenesis, and the testes development [2, 36, 37].

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