Relationship of Cytokines with Redox Status of Semen

Oxidative stress in semen has been suggested to be an important factor in the etiology of poor sperm function, especially through peroxidative damage to the sperm plasma membrane and DNA integrity in the sperm nucleus [98] . In many studies, the role of cytokines and oxidative stress in infertile patients was examined, especially together with an infection/inflammation in the genital tract [57, 85, 99, 100]. The frequent presence of leukocytes in the semen, including their major subpopulation of neutrophils, is inseparably connected with reactive oxygen intermediate (ROI) production [101, 102]. A condition in which the number of leukocytes exceeds 1 x 106/mL of semen, defined as leukocytospermia, is considered to be the threshold value above which sperm dysfunction may occur. However, rather than the leukocyte number in the semen, their activity may decide on the final effects of oxidative stress on spermatozoa [76, 103]. Many authors have observed correlations between the levels of proinflammatory cytokines and the number of leukocytes in the semen [72, 77, 104-107], However, there have been also reports demonstrating the elevated levels of proinflammatory cytokines in the semen regardless of the presence or absence of leukocytes [108, 109]. Undoubtedly, activated macrophages and neutrophils release ROIs and secrete proinflammatory cytokines, both of which can affect spermatozoa [102, 110].

Some cytokines act as regulators of the physiological levels of ROI in the seminal plasma [57, 111]. Some authors have suggested that particular cytokines modulate the expression of genes responsible for the redox system in the semen [56, 104] , Among all the cytokines, the production of chemotactic, proinflammatory cytokine IL-8 appears to be a specific response to oxidative stress. DeForge et al. [112] have demonstrated that oxidative stress is an important regulator of IL-8 gene expression in human epithelial cells and fibroblasts. Moreover, a unifying mechanism underlying this topic may involve regulation of NF-kB by the redox status of the cell, namely, its activation by ROI and its inhibition by various antioxidants in cells stimulated with cytokines or other agents like LPS or PMA [113, 114]. An increase in ROI production by human sperm was observed after the addition of IL-1a, IL-1b, or TNF-a, the result of which was an increase in sperm membrane lipid peroxidation, as measured by the malondialdehyde (MDA) level [111]. Moreover, this process has been postulated as the mechanism by which cytokines can cause infertility. It seems likely that leukocytes mediate the induction of ROS

generation by cytokines and that they have the potential to alter redox equilibrium in the semen [92]. In addition, it cannot be excluded that the oxidative stress that appears in leukocytospermia is exerted by the increased levels of cytokines themselves [105], although this has not been proved in our studies in in vitro semen inflammation conditions. However, numerous studies have demonstrated the essential interaction of proinflammatory cytokines with other mediators of inflammation to generate toxic effects at the reaction site [76, 88, 105, 115]. Some observations argue in favor of the hypothesis that interleukins do not act separately but in connection with other mediators, particularly with leukocytes [102]. In this situation, ROI (generated by leukocytes) act synergistically with proinflammatory cytokines exacerbating the destructive environment for the spermatozoa. The oxidative stress with its consequences to sperm membranes can lead to damage in sperm biological function, in spite of the fact that the semen itself consists of spermatozoa subpopulations with a different fertilizing potential.

Overproduction of reactive oxygen metabolites observed in leukocytospermia suggests a possible imbalance between ROI levels and their scavengers in the semen. Assuming that oxidative stress leads not only to an uncontrolled increase in the concentration of ROI, but also to the failure of both the enzymatic and nonenzy-matic members of the antioxidant system, we cannot exclude that some cytokines act also through changes in the activities of enzymes that normally protect the sperm against harmful metabolites. Indeed, antioxidants and the glutathione precursor have been shown in the literature to downregulate cytokine transcription and biosynthesis [116, 117]. Also, interestingly, a clear relationship between increased IL-18 and decreased GPx and selenium levels in the blood serum has been noted in patients with acute pancreatitis [118]. As for TNF-a, it may be directly positively associated with zinc concentration in the regulation of endothelial function [119]. The relationship between TNF-a levels and Mn-SOD expression in human endometrial stromal cells was also demonstrated [120]. Other authors showed inducing properties of IL-6 toward mitochondrial SOD activity [121]. Direct or indirect association between antioxidant and prooxidant activity with some interleukins present in the seminal plasma has been demonstrated in patients with genital tract inflammation [76, 105, 122] and varicocele [92]. It may be hypothesized that high activities of proinflammatory cytokines in the semen influence the intensity of oxidative stress, which may then have dangerous consequences for spermatozoa, indirectly affecting their redox profile as well as their milieu. A relationship among the cytok-ines, antioxidants, prooxidants, and semen parameters has been diligently studied in case of the semen infection/inflammation [57, 76, 105].

Pregnancy Guide

Pregnancy Guide

A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.

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