Influence of Cytokines on Sperm DNA and Apoptosis

The "poor quality" of sperm DNA appears to be one of the important factors affecting male reproductive ability [141]. This has been confirmed by numerous reports in which a high percentage of spermatozoa with fragmented DNA have been found in infertile men when compared to the fertile individuals [142, 143]. In case of inflammation of the genitourinary tract, the redox imbalance is probably the main etiological factor responsible for destructive effects of the inflammatory process on male gametes, associated with peroxidation of sperm macromolecules including DNA [100,125,144]. On the other hand, the phenomenon of oxidative stress is also associated with increased apoptosis, which leads to sperm DNA damage [145-147]. Several authors suggested an involvement of sperm apoptosis in impaired men's fertility with consequences to reduced sperm-oocyte penetration [148-150]. It is well known that some proinflammatory cytokines, such as IL-1b, TNF-a, or IL-18, take part in the regulation of the apoptotic process by the induction of the Fas/Fas ligand (FasL) system or by interaction with certain receptors, e.g., TNF-a receptor-1 [151, 152]. Participation of proinflammatory cytokines has been also suggested in the male gonad [50, 153]. It is possible that induction of sperm apoptosis can be the principal mechanism by which these proinflammatory cytokines may affect spermatozoa during the male reproductive tract infection/inflammation.

The relationship of cytokines participating in urogenital infections and human sperm apoptosis has been recently identified as a central area of interest. Of a large group of proinflammatory cytokines, IL-6 and IL-8 have been most often mentioned in the literature as the potential diagnostic markers for male genitourinary tract infections [71, 72, 76], Additionally, combinations of proinflammatory cytokines turned out to be an important factor enhancing sperm membrane lipid peroxidation primarily caused by leukocytes in the in vitro studies [88] . However, the proapop-totic properties of IL-6 or IL-8 are still unclear. Nevertheless, there are some data on induction of the lymphocyte apoptosis by proinflammatory cytokines, including IL-6, in an acute African Swine Fever infection, thus suggesting the possibility of proapoptotic activity of IL-6 exerted on the cells of the immune system ) 154]. However, the premises that IL-6 and/or IL-8 contribute to apoptosis also in ejaculated spermatozoa have not been finally clarified.

The influence ofIL-18 on apoptosis through the increase in the FasL expression has been previously documented in somatic cells. High levels of IL-18 were found, e.g., in liver inflammation, which suggests that this cytokine may regulate apopto-sis of hepatocytes and may be a reason of liver damage. There were also some reports on the possibility of IL-18-exerted apoptosis on endothelial cells and this effect was mediated by members of TNF family or the Fas/FasL system [155], Some reports have described the IL-18's harmful effects on semen quality in infertile men with urogenital infections [71], In in vitro conditions, a combination of IL-18 with IL-12 used together with leukocytes was linked with a significant increase in MDA concentrations [88]. It is possible that these inflammatory cytok-ines may cooperate with each other in apoptosis induction of mature spermatozoa (own unpublished data).

Among the various inflammatory cytokines, TNF-a is most often presented as inducer of apoptosis in human spermatozoa. Due to participation in activation of several transduction pathways, this cytokine leads to regulation of the testicular expression of several genes involved in spermatogenesis [156]. The proapoptotic effect of TNF-a can be mediated through ROI production [157, 158]. Recently, it has also been suggested that TNF-a might alter sperm function via increase in nitric oxide production [159]. TNF-a-induced apoptosis in the ejaculated spermatozoa measured by the increase of the percentage of the spermatozoa with phosphatidyl-serine (PS) externalization on the cell membrane surface and/or by the increase of the TUNEL-positive spermatozoa has been confirmed in some experimental and clinical studies [160-162] , Moreover, these proapoptotic effects were reversed in the presence of a selective anti-TNF-a antibody [160]. The proapoptotic effect of this cytokine, one of the major cytokines produced during inflammation, may explain the reduced fertilizing ability of spermatozoa obtained from men with urogenital tract inflammation.

To summarize, results of the coordinated cytokines and leukocytes action are the qualitative and quantitative changes in the oxygen metabolism of spermatozoa, which determine the magnitude of toxic interactions of oxygen with cellular macromole-cules (such as lipids or DNA). The course of the inflammatory process and its influence on the function of sperm depends on the type of initiating factor, time of exposition of inflammatory mediators, and the initial condition of the antioxidative system in the semen. Evaluation of the damage to cellular membranes or the integrity of sperm DNA seems to be an extremely important information for the prognosis of the male gamete fertilizing ability and may be an important step toward establishing new, additional diagnostic algorithms, which will pave the way to conservative treatment of male infertility (by antioxidants) as well as better qualification and selection of assisted reproduction techniques.

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