Repertoire of Cytokines in Seminal Plasma

In the male gonad, cytokines are produced physiologically and are involved in the normal function of the organ [30, 49, 50]. In this respect, they must also appear as natural components of seminal plasma [51]. A network of cytokines, chemokines, and growth factors, such as interleukins (ILs), IL-1a and -1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-13, IL-17, and IL-18, their soluble receptors and antagonists (e.g., IL-1RA, sR IL-2, sR IL-6), TNF-a, transforming growth factor (TGF) family of cytokines (TGF-a and -b), interferon gamma (IFN-g), granulocyte colony-stimulating factor (G-SCF), granulocyte-macrophage colony-stimulating factor (GM-SCF), and macrophage inflammatory proteins alpha (MIP-1a) and beta (MIP-b), was shown to be present in human semen [51, 52]. The nature, precise origin, and regulation of the cytokines in the male genital tract are still under investigation. The main sources of cytokines occurring in the male reproductive tract are testes and, among others, testicular macrophages, although some cytokines (IL-1,

IL-6) are also produced by somatic cells in testis, including the Leydig and Sertoli cells [27]. However, some studies also indicated local production of these factors in the secondary sex glands irrespective of spermatogenesis [53, 54]. Cytokines appear to be also secreted by the epididymis and the prostate gland [55] . Prostate gland, for example, seems to be the main site of origin of IL-6 and IL-2 in the seminal plasma [54, 56-58]. Moreover, the significant correlation between IL-6 and fructose levels observed suggests that the seminal vesicles can be also included in the production of this cytokine [58] . According to some authors, in the male genital system, some cytokines (IL-1 and IL-6) can be produced and secreted not only by somatic cells, but also by germ cells [59, 60]. It is possible that cytokines may act not only as an autocrine factor, but also in a paracrine manner during spermatogenesis, sperm maturation, sperm transport, and even during the fertilization process [61]. Finally, cytokines are released by various immunocompetent cells present in the male genital tract, which are the major source of these factors produced in response to foreign antigens, pathogens, and also in semen inflammation [62]. A lot of in vivo studies on the effects of cytokines and growth factors on sperm function have provided somewhat controversial results. On the one hand, cytokines and other immune factors are intrinsically involved in normal reproductive physiology, but on the other hand their local or systemic perturbations underlie pathophysiology of sperm function. A cytokine network may play an important role in immunoregulatory effects in human semen of both fertile and infertile men. There are several topics of cytokine research in the male reproductive system: (1) presence of various cytokines in human seminal plasma, (2) demonstration of differences in cytokine concentrations between fertile and infertile men, (3) presence of negative correlations between cytokine levels and semen parameters, (4) demonstration of correlations between cytokine levels and leukocyte count, and (5) usefulness of some cytokines as clinical markers of male infertility.

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