[Frontiers in Bioscience E3, 89-95, January 1, 2011]
Impact of inflammation on male fertility
Oli Sarkar1, 3, Jamila Bahrainwala2, Sambamurthy Chandrasekaran2, Shiva Kothari2, Premendu P. Mathur1, Ashok Agarwal2
1
TABLE OF CONTENTS
1. ABSTRACT
The male uro-genital tract is susceptible to gram-negative bacterial infections that produce a state of inflammation, particularly in the testis and epididymis. Development of germline stem cells into motile spermatozoa takes place in these organs and thus any impairment therein has a direct effect on male fertility. A number of factors are known to impair male fertility including environmental and chemical factors, lifestyle, and infections. The last is a little-known and poorly understood cause of male sub-/ infertility. The presence of the pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF- alpha> ), interleukin-1alpha (IL-1alpha) and interleukin-1beta (IL-1beta) in the male uro-genital tract following bacterial infections suggests that such infections could have cytokine-mediated anti-fertility effects. Furthermore, inflammation has been associated with elevated levels of reactive oxygen species and oxidative stress both of which affect male fertility. The present article summarizes the effects of inflammation on the testis, epididymis and spermatozoa. We review the correlations between inflammation and oxidative stress vis-à-vis spermatogenesis and discuss the implications of infections on male fertility/ infertility and assisted reproductive technologies for the male.
2. INTRODUCTION
At the start of spermatogenesis, spermatogonia, or immature germ cells divide mitotically to produce diploid cells termed spermatocytes. Spermatocytes undergo two mitotic divisions as they migrate from the base of Sertoli cells to the top or apical end. The meiotic division involves pairs of chromosomes coming together and exchanging DNA to form secondary spermatocytes. Subsequently, the two chromatids separate and form haploid cells called spermatids. These spermatids are then released from the testes into the epididymis where they begin to undergo capacitation and acquire motility (1, 2). Spermatids, now called spermatozoa are thus motile and possess the requirements for their trajectory in the female reproductive tract (3-6). The last leg of capacitation occurs in the cervix where spermatozoa attain hyperactivity and which is the site of acrosomal reaction. The acrosomal reaction enables the spermatozoon to penetrate the zona pellucida, fuse with the oolema and cause fertilization. Thus, male fertility is directly dependent on the uninterrupted completion of spermatogenesis.
Infertility in males is fundamentally due to disruption in the process of spermatogenesis resulting in no or incompetent spermatozoa (7, 8). Different spermatogenic factors or "symptoms" are considered to lead to infertility such as decreased sperm motility, low sperm count, damage to sperm DNA, and/ or poor semen quality. Seminal quality can be compromised due to a number of factors like high levels of reactive oxygen species (ROS) and oxidative stress (7, 9, 10). Oxidative stress has been known to affect spermatogenesis in the testis, epididymis and at a seminal level (11, 12). In the past few years, new evidence suggests that oxidative stress in the testis can be linked to inflammatory conditions therein (13).
Inflammation is the body's defense against infection or injury where there is an increase in local blood flow, micro-vascular permeability and recruitment of leukocytes to the site of infection. Inflammatory response can be either acute or chronic depending upon the severity and time taken for response. Briefly, inflammatory response starts with hemodynamic changes (like vasodilatations and increased vascular permeability) that facilitate the emigration of circulating leukocytes into the infection site. Leukocytes phagocytose or kill microbes and digest tissue debris and thus protect the host. Cytokines such as interleukins (IL) and tumor necrosis factors (TNFs) are involved in signal transduction during states of inflammation. Inflammation is caused by a number of factors chief among which are infections by gram-negative bacteria. Lipopolysaccharide (LPS), present in the cell wall of gram-negative bacteria is considered to be the endotoxic element that causes inflammation (14). Since the male is susceptible to a number of uro-genital tract infections that cause a state of inflammation in the reproductive tract, it is relevant to know the potential effects of inflammation on the male reproductive system. The present article summarizes the effects of inflammation on the testis, epididymis and spermatozoa, specifically mediated by a few pro-inflammatory cytokines TNF-alpha, IL-1alpha and IL-1beta. We review the correlations between inflammation and oxidative stress vis-à-vis spermatogenesis. We highlight some important markers of inflammation in the semen and discuss the implications of infections on male fertility/ infertility and assisted reproductive technologies for the male.
3. FFECTS OF INFLAMMATION ON MALE REPRODUCTIVE SYSTEM
Inflammation has been known to affect the twin testicular functions of steroidogenesis and spermatogenesis. Marked decreases in the circulating levels of luteinizing hormone and testosterone are detected when there is inflammation (15-17). When bacterial inflammation is induced by injecting LPS, there are decreased testosterone levels due to a reduction in the activity of Steroid Acute Regulatory (StAR) protein, a key regulator of steroidogenesis (18). The co-occurrence of high levels of pro-inflammatory cytokines (like IL-1beta, TNF-alpha) with the inhibition of StAR protein activity suggests cross-talk between these cytokines and StAR protein (18-20). A recent study found that inflammation caused spermatogenic arrest and deceleration in sperm maturational processes (21). Interestingly, inflammation has a cell-specific effect on various germ cells. Spermatocytes and spermatids seem to be primarily affected while spermatogonia are often seen to be unaffected (21). Although a number of studies report inflammation in the epididymis, it is difficult to ascertain whether this is a consequence of testicular effects or if the epididymis can be the primary target of inflammation. In conditions of epididymal inflammation, the count and motility of caudal sperm are decreased and often there is obstructive azoospermia. Inflammation affects the prostate by suppressing the secretion of citric acid and gamma-glutamyl transpeptidase by the gland. Most importantly, in conditions of inflammation, there is infiltration of leucocytes into semen and production of anti-sperm antibodies. Inflammatory conditions increase rigidity of sperm flagellar membrane by decreasing lipid content of the membrane. This decreases sperm motility and causes sperm agglutination and asthenozoospermia (22, 23). Ensuing defects in acrosome reaction render the sperm incapable of penetrating the oolemma. Moreover, the integrity of sperm DNA is damaged leading to an increase in the number of apoptotic sperm (24). Sperm or germ cell apoptosis is regulated by ROS and related to the oxidant/ antioxidant status of the testis (25).
4. INFLAMMATION: A CAUSE OXIDATIVE STRESS
Prior to discussing the correlation between inflammation and oxidative stress, it is necessary to understand the importance of the oxidant/ antioxidant system and its role in spermatogenesis. ROS like hydrogen peroxide (H2O2), hydroxyl radical (OH), and superoxide anion (O2-) are highly reactive oxygen free radicals which contain one of more unpaired electrons (8). Small amounts of ROS are required for capacitation, hyperactivation, and acrosome reaction, and sperm-oocyte fusion (26). However, ROS, in high amounts, can be harmful to sperm as these radicals try to poach hydrogen atoms from polyunsaturated fatty acid of sperm membrane in order to fill their valence (27). ROS take up the hydrogen atoms causing peroxidation of membrane lipids, loss of adenosine triphosphate (ATP), and loss of membrane fluidity and integrity (28-30). The reduction in intracellular ATP compromises axonemal protein phosphorylation leading to sperm immobilization (31). Antioxidants act as defense mechanisms against the pathological effects of ROS production and oxidative stress (32).
To prevent excesses of ROS and maintain a balance, cells contain a number of antioxidants that degrade ROS to form non-radical molecules like water (33). Antioxidants are of two types: (i) enzymatic and (ii) non-enzymatic antioxidants. Three main enzymatic antioxidants include superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX). SOD converts the superoxide anion to H2O2. Both catalase and GPX neutralize H2O2 into water and oxygen. Three main non-enzymatic antioxidants include glutathione, Vitamin C and Vitamin E. Glutathione and Vitamin C directly neutralize ROS while Vitamin E is required to recycle Vitamin C (34). Spermatozoal antioxidant defense mechanisms are important because spermatozoa contain very little cytoplasm (approximately 20 μm3), which is the cellular depot of antioxidants and thus makes the spermatozoa a vulnerable target of oxidative damage (35). To compensate for this lack of cytoplasm, the semen is a rich storehouse of antioxidants (36).
As briefly mentioned in the introduction section, there is evidence that suggests that in the semen, inflammation could be linked to oxidative stress. Infertile men with high levels of seminal ROS showed increased levels of pro-inflammatory cytokines and leukocyte infiltration in their semen (37). Although certain invading pathogens such as bacteria may produce ROS themselves, leukocytes are considered to be the predominant source of ROS in semen (38, 39). They do so in two ways: (i) directly, or (ii) indirectly by increasing the levels of inflammatory cytokines which then cause an increase in ROS levels (40, 41). In the "direct pathway", phagocytes are activated and as phagocytosis proceeds, there is production of large amounts of ROS (like superoxide anion, hydrogen peroxide, hydroxyl radical and hypochlorite) in oxidative bursts (42, 43). These ROS are either produced in the semen or within the leukocyte itself, and react with spermatozoal membrane. Due to the oxidative burst, oxidants outnumber antioxidants, inducing a state of oxidative stress (44). This state of oxidative stress persists even after the removal of the pathogen (23). Interestingly, in males who were infertile prior to induction of inflammation, the imbalance between oxidants and antioxidants was more drastic suggesting that inflammation induced by oxidative burst could be an important confounder of male infertility (45).
5. CYTOKINES
The second pathway of oxidative stress generation is by the generation of pro-inflammatory cytokines by leukocytes (44). Cytokines, in general, are proteins that can act as signaling molecules and that can modulate cellular reactions like inflammation (24, 43, 46). They activate the xanthine oxidase system giving rise to high levels of ROS and oxidative stress (23). Cytokines induce an inflammatory response by binding to their receptors and stimulating a signal transduction involving tyrosine or serine phosphorylation. This leads to the activation of transcription factors, which are then able to modulate gene expression. Furthermore, cytokines generally work synergistically and have a greater impact when interacting with each other to create a complex network enabling cells to react to the pathogen invasion in a systematic fashion (43, 46). There are a number of cytokines that mediate the effects of inflammation in the male reproductive tract, but the most important ones are tumor necrosis factors (TNFs) and interleukins (ILs) (47).
5.1. TNF- alpha
Tumor necrosis factor- alpha (TNF-alpha) is a 17kDa protein secreted mainly by activated T cells, monocytes, macrophages, and a few non-lymphoid cells like Sertoli and male germ cells. TNF-alpha binds to a transmembrane receptor, TNF receptor, which then recruits several cytosolic proteins and transduces the signal. In the testis, TNF-alpha regulates germ cell apoptosis, Sertoli cell-germ cell junction dynamics and Leydig cell steroidogenesis (48). TNF- alpha represses gene expression of steroidogenic enzyme in Leydig cells via activation of nuclear factor kappaB (49-51). The repression of the steroidogenic enzymes leads to a decrease in testosterone production (50). Increase in the levels of testosterone causes germ cell depletion from the epithelium (52). High levels of TNF-alpha have also been detected in the semen of sub-fertile and infertile men. In fact, a recent study reports the presence of high seminal levels of TNF-alpha in conditions of leukocyte infiltration of semen and shows that inflammation-mediated azoospermia is directly related to seminal levels of TNF-alpha (53, 54).
5.2. IL-1 alpha
Interleukin-1alpha (IL-1alpha) is a 17 kDa growth factor, acts as a co-stimulator of T cell functions, is involved in the activation and differentiation of leukocytes, and in Sertoli cell proliferation (43, 47, 55-57). IL-1alpha is secreted by Sertoli cells and germ cells in an age- and cell type-dependent manner (58). IL-1alpha is present in large amounts in secondary spermatocytes and is shed with residual body when the germ cells differentiate into spermatids (59). In response to testicular inflammation stimulated by chemicals (like zymosan) or pathogens (LPS from gram-negative bacteria), testicular macrophages secrete increased quantities of IL-1alpha (60). The secretion of this cytokine leads to inhibition of Leydig cell steroidogenesis, stimulation of Sertoli cell transferrin and IL-6 production (61-63). IL-1alpha has been shown to downregulate testicular cell adhesion and to have a role in cell-cell cross-talk. A recent report suggests that IL-1alpha may be a previously ignored regulator of the blood-testis barrier and may thus be intricately linked with the immune-privileged status of the seminiferous tubules (64).
5.3. IL-1beta
IL-1beta is involved in regulation of spermatogenesis and spermiogenesis but in high amounts is cytotoxic to germ cells (43). An interesting characteristic of IL-1beta is that it is a paracrine as well as an autocrine substance that serves as an important mediator of immunologic and pathologic responses to conditions of stress, antigenic challenges, and infection (65). For example, when bacterial infections were simulated by treating with LPS, there was an increase in the expression IL-1beta concomitant with a decrease in testosterone levels. Thus, the ensuing loss of spermatogenesis could be either due to the direct effect of inflammation or due to inflammation-induced decrease in testosterone production (43, 66). IL-1beta has been shown to decrease semen quality, sperm count and motility (67). IL-1beta signals an increase in expression of adhesion molecules and receptors so that the leukocytes can attach to the blood vessel and reach the site of infection (57). It is interesting to note that high IL-1beta levels were detected in semen although it is completely sealed off from circulation (68).
6. SEMINAL MARKERS OF INFLAMMATION
According to the World Health Organization human semen is normal if the leukocyte count is below one million per milliliter (69). If the number of leukocytes exceeds one million, spermatozoa are damaged and the condition is called leukocytospermia (27). The main leukocytes that infiltrate semen are granulocytes and T lymphocytes (70). Granulocytes generally make up the largest leukocyte type in seminal fluid (50-60%), followed by T lymphocytes (2-5%) (41, 71). Leukocytospermia has been associated with the impairment of various seminal parameters such as decreased sperm motility, ability of sperm to penetrate zona pellucida, impaired fertilizing capability, and decreased viability due to their ability to induce ROS (72, 73)}. Leukocytocytes and macrophages migrate to the semen when there is pathogen- or tissue damage-induced inflammation (24, 41, 74). The oxygen metabolism of the leukocytes accelerates and is connected with the production and release of large amounts of superoxide anion and hydrogen peroxide (43). Thus, leukocytes are the most obvious markers of inflammation in the semen.
Inflammation in the male reproductive tract is an equally important indicator of inflammation in the semen. As previously discussed, cytokines can induce inflammation directly and are also a part of leukocyte-mediated inflammatory defense. A positive correlation between the levels of different cytokines and the presence of leukocytes have recently been demonstrated in semen. Increased levels of IL-8 and TNF-alpha were detected in semen contaminated with pathogens and showing a high leukocyte count (53). However, high IL-6 levels were seen in leukocyte-infiltrated semen, even in the absence of pathogens suggesting that IL-6 could also be used as an indicator of non-pathogenic inflammation in the semen (53). Most interesting is the study by Seshadri et al who show that men with different seminal defects have different cytokine profiles. For example, sub-fertile men who were oligospermic (low sperm count) had increased levels of IL-6 and IL-10 levels, whereas those who were asthenospermic (low sperm motility) had increased IL-8 and IL-10 in their semen. In sub-fertile men with obstructive azoospermia (due to blockage in the reproductive tract) the levels of IL-6, IL-10 and TNF-alpha were high (54). These studies clearly show that cytokine profiling in the semen could be used as a method to detect inflammation in the reproductive tract and infections especially in the scenarios like assisted reproductive therapies (ART), where it is necessary to minimize genetic defects transmitted due to selection of poor quality sperm.
7. INFLAMMATION AND ASSISTED REPRODUCTION
When men opt for assistance for sub-/ infertility, they are examined for general health and infections. Reports suggest that even if the male reproductive tract is under inflammation, viable sperm may be selectively harvested and used for ART like in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) (75). However, the accidental selection of damaged sperm is high and can have the following consequences: (i) sperm with improper DNA organization or chromatin condensation could cause defects in the fetus and in the offspring (28), (ii) sperm with fragmented DNA, which are able to fertilize the oocyte could lead to embryonic development stops resulting in failed pregnancy or spontaneous abortion when paternal genes are switched on (76), (iii) sperm with damaged DNA could lead to poor quality of blastocysts, sub-optimal pregnancy rates, and an increase in miscarriage (22), (iv) fertilization of oocyte with sperm damaged by ROS (seen during inflammation) could be a possible cause of neonatal cancers in the offspring (9). However, it is still not clear if this is due to the direct effects of leukocyte infiltration-induced inflammation or is a result of ROS-induced apoptosis (76-78). Despite the number of studies which show the detrimental effect of inflammation in the male reproductive tract on ART, currently there are no definite methods to overcome this setback and subjects are thus advised against ART till they are normal.
8. CONCLUSIONS
Inflammation of the male reproductive tract is mediated chiefly by cytokines like TNF-alpha and Interleukins. In the testis, inflammation affects Sertoli cells (causing a loss of blood-testis barrier function and immune-privilege status) and Leydig cells (causing a decrease in testosterone production) and resulting in "arrested spermatogenesis". Seminal contamination by pro-inflammatory agents impairs sperm morphology and physiology leading to sub/ infertility. The use of assisted reproductive technologies could give sub/ infertile men suffering from infection-induced inflammation a chance for a successful fatherhood. However, a number of long-term and holistic studies are needed before such therapies can be prescribed.
9. REFERENCES
1. L. D. Russell: Movement of spermatocytes from the basal to the adluminal compartment of the rat testis. Am J Anat, 148, 313-328 (1977)
2. M. Dym: Spermatogonial stem cells of the testis. Proc Natl Acad Sci U S A, 91(24), 11287-9 (1994)
3. R. Goldman, E. Ferber and U. Zort: Reactive oxygen species are involved in the activation of cellular phospholipase A2. FEBS Lett, 309(2), 190-2 (1992)
4. E. de Lamirande and C. Gagnon: Human sperm hyperactivation and capacitation as parts of an oxidative process. Free Radic Biol Med, 14(2), 157-66 (1993)
5. P. Leclerc, E. de Lamirande and C. Gagnon: Regulation of protein-tyrosine phosphorylation and human sperm capacitation by reactive oxygen derivatives. Free Radic Biol Med, 22(4), 643-56 (1997)
6. K. Toshimori: Dynamics of the Mammalian Sperm Head. In: Advances in Anatomy, Embryology and Cell Biology. Ed K. Toshimori. Springer Berlin Heidelberg, Berlin (2009)
7. R. J. Aitken and J. S. Clarkson: Cellular basis of defective sperm function and its association with the genesis of reactive oxygen species by human spermatozoa. J Reprod Fertil, 81(2), 459-69 (1987)
8. S. C. Sikka: Relative impact of oxidative stress on male reproductive function. Curr Med Chem, 8(7), 851-62 (2001)
9. R. J. Aitken: The Amoroso Lecture. The human spermatozoon--a cell in crisis? J Reprod Fertil, 115(1), 1-7 (1999)
10. J. S. Armstrong, M. Rajasekaran, W. Chamulitrat, P. Gatti, W. J. Hellstrom and S. C. Sikka: Characterization of reactive oxygen species induced effects on human spermatozoa movement and energy metabolism. Free Radic Biol Med, 26(7-8), 869-80 (1999)
11. A. Agarwal and R. A. Saleh: Role of oxidants in male infertility: rationale, significance, and treatment. Urol Clin North Am, 29(4), 817-27 (2002)
12. B. Saradha and P. P. Mathur: Oxidative stress and male reproduction. In: Hormone Biotechnology. Ed S. K. Maitra. Daya Publishing House, Delhi (2007)
13. M. M. Reddy, S. V. Mahipal, J. Subhashini, M. C. Reddy, K. R. Roy, G. V. Reddy, P. R. Reddy and P. Reddanna: Bacterial lipopolysaccharide-induced oxidative stress in the impairment of steroidogenesis and spermatogenesis in rats. Reprod Toxicol, in press (2006)
14. M. Cutolo, E. Balleari, M. Giusti, M. Monachesi and S. Accardo: Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation. Arthritis Rheum, 31(10), 1314-7 (1988)
15. M. Cutolo, E. Balleari, M. Giusti, E. Intra and S. Accardo: Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum, 34(1), 1-5 (1991)
16. M. Wallgren, H. Kindahl and H. Rodriguez-Martinez: Alterations in testicular function after endotoxin injection in the boar. Int J Androl, 16(3), 235-43 (1993)
17. M. K. O'Bryan, S. Schlatt, O. Gerdprasert, D. J. Phillips, D. M. de Kretser and M. P. Hedger: Inducible nitric oxide synthase in the rat testis: evidence for potential roles in both normal function and inflammation-mediated infertility. Biology of Reproduction, 63(5), 1285-93 (2000)
18. D. B. Hales: Interleukin-1 inhibits Leydig cell steroidogenesis primarily by decreasing 17 alpha-hydroxylase/C17-20 lyase cytochrome P450 expression. Endocrinology, 131(5), 2165-72 (1992)
19. T. Lin, T. L. Wang, M. L. Nagpal, J. H. Calkins, W. W. Chang and R. Chi: Interleukin-1 inhibits cholesterol side-chain cleavage cytochrome P450 expression in primary cultures of Leydig cells. Endocrinology, 129(3), 1305-11 (1991)
20. T. Lin, D. Wang and D. M. Stocco: Interleukin-1 inhibits Leydig cell steroidogenesis without affecting steroidogenic acute regulatory protein messenger ribonucleic acid or protein levels. J Endocrinol, 156(3), 461-7 (1998)
21. S. H. Liew, S. J. Meachem and M. P. Hedger: A stereological analysis of the response of spermatogenesis to an acute inflammatory episode in adult rats. J Androl, 28(1), 176-85 (2007)
22. K. Tremellen: Oxidative stress and male infertility--a clinical perspective. Hum Reprod Update, 14(3), 243-58 (2008)
23. D. Sanocka, P. Jedrzejczak, A. Szumala-Kaekol, M. Fraczek and M. Kurpisz: Male genital tract inflammation: The role of selected interleukins in regulation of pro-oxidant and antioxidant enzymatic substances in seminal plasma. J Androl, 24(3), 448-55 (2003)
24. F. H. Comhaire, A. M. Mahmoud, C. E. Depuydt, A. A. Zalata and A. B. Christophe: Mechanisms and effects of male genital tract infection on sperm quality and fertilizing potential: the andrologist's viewpoint. Hum Reprod Update, 5(5), 393-8 (1999)
25. S. Vaithinathan, B. Saradha and P. P. Mathur: Methoxychlor induces apoptosis via mitochondria- and FasL-mediated pathways in adult rat testis. Chem Biol Int, In press, DOI: 10.1016/j.cbi.2010.03.014 (2010)
26. E. de Lamirande, H. Jiang, A. Zini, H. Kodama and C. Gagnon: Reactive oxygen species and sperm physiology. Rev Reprod, 2(1), 48-54 (1997)
27. R. J. Aitken: Free radicals, lipid peroxidation and sperm function. Reprod Fertil Dev, 7(4), 659-68 (1995)
28. J. P. Twigg, D. S. Irvine and R. J. Aitken: Oxidative damage to DNA in human spermatozoa does not preclude pronucleus formation at intracytoplasmic sperm injection. Hum Reprod, 13(7), 1864-71 (1998)
29. E. de Lamirande and C. Gagnon: Reactive oxygen species and human spermatozoa. I. Effects on the motility of intact spermatozoa and on sperm axonemes. J Androl, 13(5), 368-78 (1992)
30. E. de Lamirande and C. Gagnon: Reactive oxygen species and human spermatozoa. II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility. J Androl, 13(5), 379-86 (1992)
31. S. Walrand, S. Valeix, C. Rodriguez, P. Ligot, J. Chassagne and M. P. Vasson: Flow cytometry study of polymorphonuclear neutrophil oxidative burst: a comparison of three fluorescent probes. Clin Chim Acta, 331(1-2), 103-10 (2003)
32. S. C. Sikka: Oxidative stress and role of antioxidants in normal and abnormal sperm function. Front Biosci, 1, e78-86 (1996)
33. J. F. Griveau and D. Le Lannou: Reactive oxygen species and human spermatozoa: physiology and pathology. Int J Androl, 20(2), 61-9 (1997)
34. J. C. Kefer, A. Agarwal and E. Sabanegh: Role of antioxidants in the treatment of male infertility. Int J Urol, 16(5), 449-57 (2009) doi:IJU2280 (pii)
35. L. O. Drevius: Bull spermatozoa as osmometers. J Reprod Fertil, 28(1), 29-39 (1972)
36. A. Agarwal, K. Makker and R. Sharma: Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol, 59(1), 2-11 (2008) doi:AJI559 (pii)
37. R. D'Agata, E. Vicari, M. L. Moncada, G. Sidoti, A. E. Calogero, M. C. Fornito, G. Minacapilli, A. Mongioi and P. Polosa: Generation of reactive oxygen species in subgroups of infertile men. Int J Androl, 13(5), 344-51 (1990)
38. J. E. Hong, L. A. Santucci, X. Tian and D. J. Silverman: Superoxide dismutase-dependent, catalase-sensitive peroxides in human endothelial cells infected by Rickettsia rickettsii. Infect Immun, 66(4), 1293-8 (1998)
39. J. M. Potts and F. F. Pasqualotto: Seminal oxidative stress in patients with chronic prostatitis. Andrologia, 35(5), 304-8 (2003)
40. K. Whittington and W. C. Ford: Relative contribution of leukocytes and of spermatozoa to reactive oxygen species production in human sperm suspensions. Int J Androl, 22(4), 229-35 (1999)
41. H. Wolff: The biologic significance of white blood cells in semen. Fertil Steril, 63(6), 1143-57 (1995)
42. D. R. Blake, R. E. Allen and J. Lunec: Free radicals in biological systems--a review orientated to inflammatory processes. Br Med Bull, 43(2), 371-85 (1987)
43. M. Fraczek and M. Kurpisz: Inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa. J Androl, 28(2), 325-33 (2007)
44. M. Rajasekaran, W. J. Hellstrom, R. K. Naz and S. C. Sikka: Oxidative stress and interleukins in seminal plasma during leukocytospermia. Fertil Steril, 64(1), 166-71 (1995)
45. D. Sanocka, M. Fraczek, P. Jedrzejczak, A. Szumala-Kakol and M. Kurpisz: Male genital tract infection: an influence of leukocytes and bacteria on semen. J Reprod Immunol, 62(1-2), 111-24 (2004) doi:10.1016/j.jri.2003.10.005
46. F. R. Ochsendorf: Infections in the male genital tract and reactive oxygen species. Hum Reprod Update, 5(5), 399-420 (1999)
47. M. Feldmann and J. Saklatvala: Proinflammatory cytokines. In: Cytokine Reference. Ed J. Oppenheim&F. M. Academic Press, New York (2001)
48. W. Xia, D. D. Mruk, W. M. Lee and C. Y. Cheng: Cytokines and junction restructuring during spermatogenesis--a lesson to learn from the testis. Cytokine Growth Factor Rev, 16(4-5), 469-93 (2005)
49. M. K. Y. Siu, D. D. Mruk, W. M. Lee and C. Y. Cheng: Adhering junction dynamics in the testis are regulated by an interplay of beta 1-integrin and the focal adhesion complex-associated proteins. Endocrinology, 144, 2141-2163 (2003)
50. C. Y. Hong, J. H. Park, R. S. Ahn, S. Y. Im, H. S. Choi, J. Soh, S. H. Mellon and K. Lee: Molecular mechanism of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha. Mol Cell Biol, 24(7), 2593-604 (2004)
51. V. Pentikainen, K. Erkkila, L. Suomalainen, M. Otala, M. O. Pentikainen, M. Parvinen and L. Dunkel: TNFalpha down-regulates the Fas ligand and inhibits germ cell apoptosis in the human testis. J Clin Endocrinol Metab, 86(9), 4480-8 (2001)
52. K. Mealy, B. Robinson, C. F. Millette, J. Majzoub and D. W. Wilmore: The testicular effects of tumor necrosis factor. Ann Surg, 211(4), 470-5 (1990)
53. E. Martinez-Prado and M. I. Camejo Bermudez: Expression of IL-6, IL-8, TNF-alpha, IL-10, HSP-60, anti-HSP-60 antibodies, and anti-sperm antibodies, in semen of men with leukocytes and/or bacteria. Am J Reprod Immunol, 63(3), 233-43
54. S. Seshadri, M. Bates, G. Vince and D. I. Jones: The role of cytokine expression in different subgroups of subfertile men. Am J Reprod Immunol, 62(5), 275-82 (2009)
55. C. Cudicini, H. Lejeune, E. Gomez, E. Bosmans, F. Ballet, J. Saez and B. Jégou: Human Leydig cells and Sertoli cells are producers of Interleukins-1 and -6. J Clin Endocrinol Metab, 82(5), 1426-33 (1997)
56. M. Huleihel, E. Lunenfeld, S. Horowitz, A. Levy, G. Potashnik and M. Glezerman: Production of interleukin-1-like molecules by human sperm cells. Fertility and Sterility, 73(6), 1132-1137 (2000)
57. C. A. Dinarello: Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol, 27, 519-50 (2009)
58. J. P. Stephan, V. Syed and B. Jegou: Regulation of Sertoli cell IL-1 and IL-6 production in vitro. Mol Cell Endocrinol, 134(2), 109-18 (1997)
59. N. Gerard, V. Syed and B. Jegou: Lipopolysaccharide, latex beads and residual bodies are potent activators of Sertoli cell interleukin-1 alpha production. Biochem Biophys Res Commun, 185(1), 154-61 (1992)
60. K. Svechnikov, C. Petersen, T. Sultana, A. Wahlgren, C. Zetterstrom, E. Colon, C. Bornestaf and O. Soder: The paracrine role played by interleukin-1 alpha in the testis. Current Drug Targets - Immune Endocrine & Metabolic Disorders, 4(1), 67-74 (2004)
61. J. H. Calkins, H. Guo, M. M. Sigel and T. Lin: Tumor necrosis factor-alpha enhances inhibitory effects of interleukin-1 beta on Leydig cell steroidogenesis. Biochem Biophys Res Commun, 166(3), 1313-8 (1990)
62. M. Huleihel, D. Zeyse, E. Lunenfeld, M. Zeyse and M. Mazor: Induction of transferrin secretion in murine Sertoli cells by FSH and IL-1: the possibility of different mechanism(s) of regulation. Am J Reprod Immunol, 47(2), 112-7 (2002)
63. V. Syed, J. P. Stephan, N. Gérard, A. Legrand, M. Parvinen, C. W. Bardin and B. Jégou: Residual bodies activate Sertoli cell interleukin-1 alpha (IL-1 alpha) release, which triggers IL-6 production by an autocrine mechanism, through the lipoxygenase pathway. Endocrinology, 136(7), 3070-8 (1995)
64. O. Sarkar, P. P. Mathur, C. Y. Cheng and D. D. Mruk: Interleukin 1 alpha (IL1A) is a novel regulator of the blood-testis barrier in the rat. Biol Reprod, 78(3), 445-54 (2008)
65. W. Eggert-Kruse, I. Kiefer, C. Beck, T. Demirakca and T. Strowitzki: Role for tumor necrosis factor alpha (TNF-alpha) and interleukin 1-beta (IL-1beta) determination in seminal plasma during infertility investigation. Fertil Steril, 87(4), 810-23 (2007)
66. C. Petersen, B. C, F. B and S. O: Interleukin-1 is a potent growth factor for immature rat sertoli cells. Mol Cell Endocrinol, 186(1), 37-47 (2002)
67. M. S. Gruschwitz, R. Brezinschek and H. P. Brezinschek: Cytokine levels in the seminal plasma of infertile males. J Androl, 17(2), 158-63 (1996)
68. J. Jiwakanon, M. Berg, E. Persson, C. Fossum and A. M. Dalin: Cytokine expression in the gilt oviduct: Effects of seminal plasma, spermatozoa and extender after insemination. Anim Reprod Sci
69. R. J. Aitken, D. Buckingham, K. West, F. C. Wu, K. Zikopoulos and D. W. Richardson: Differential contribution of leucocytes and spermatozoa to the generation of reactive oxygen species in the ejaculates of oligozoospermic patients and fertile donors. J Reprod Fertil, 94(2), 451-62 (1992)
70. W. Krause, C. Bohring, A. Gueth, S. Horster, A. Krisp and J. Skrzypek: Cellular and biochemical markers in semen indicating male accessory gland inflammation. Andrologia, 35(5), 279-82 (2003)
71. D. J. Anderson: Cell-mediated immunity and inflammatory processes in male infertility. Arch Immunol Ther Exp (Warsz), 38(1-2), 79-86 (1990)
72. J. A. Hill, J. Cohen and D. J. Anderson: The effects of lymphokines and monokines on human sperm fertilizing ability in the zona-free hamster egg penetration test. Am J Obstet Gynecol, 160(5 Pt 1), 1154-9 (1989)
73. H. Wolff, J. A. Politch, A. Martinez, F. Haimovici, J. A. Hill and D. J. Anderson: Leukocytospermia is associated with poor semen quality. Fertil Steril, 53(3), 528-36 (1990)
74. M. I. el-Demiry, T. B. Hargreave, A. Busuttil, K. James, A. W. Ritchie and G. D. Chisholm: Lymphocyte sub-populations in the male genital tract. Br J Urol, 57(6), 769-74 (1985)
75. H. W. Baker: Management of male infertility. Baillieres Best Pract Res Clin Endocrinol Metab, 14(3), 409-22 (2000)
76. D. Sakkas, E. Mariethoz, G. Manicardi, D. Bizzaro, P. G. Bianchi and U. Bianchi: Origin of DNA damage in ejaculated human spermatozoa. Rev Reprod, 4(1), 31-7 (1999)
77. R. Henkel, G. Maass, M. Hajimohammad, R. Menkveld, T. Stalf, J. Villegas, R. Sanchez, T. F. Kruger and W. B. Schill: Urogenital inflammation: changes of leucocytes and ROS. Andrologia, 35(5), 309-13 (2003)
78. H. M. Shen, J. Dai, S. E. Chia, A. Lim and C. N. Ong: Detection of apoptotic alterations in sperm in subfertile patients and their correlations with sperm quality. Hum Reprod, 17(5), 1266-73 (2002)
Key Words: Infertility, Inflammation, Oxidative Stress, Cytokine, Sperm, Review
Send correspondence to: Ashok Agarwal, Center for Reproductive Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk A19.1, Cleveland, Ohio 44195, USA, Tel: 216-444-9485, Fax: 216-445-6049, E-mail: Agarwaa@ccf.org