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From the Institute of Human Genetics, Polish Academy of Sciences,
Pozna
, Poland.
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Correspondence to: Prof Maciej Kurpisz, Institute of Human Genetics, Polish
Academy of Sciences, ul. Strzeszyska 32, 60-479 Pozna, Poland
(e-mail:
kurpimac{at}man.poznan.pl). |
| Received for publication July 3, 2006; accepted for publication October 30, 2006. |
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Abstract |
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 Top Abstract Kinetics of the Inflammatory...BacteriaLeukocytesProinflammatory CytokinesConclusionsReferences |
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Key words: Inflammatory factors, reactive oxygen species, peroxidative damage, semen
The processes that are crucial for fertilization, such as sperm hyperactivation, phosphorylation of tyrosine kinases during sperm capacitation, and the activation of cellular phospholipase A2 in the acrosomal reaction, are strictly regulated by the redox system of spermatozoa (Goldman et al, 1992; de Lamirande and Gagnon, 1993; Leclerc et al, 1997). The same reactive oxygen species (ROS) that under physiological conditions are an inseparable element of the fertilization process, as well as being important regulatory factors in the control of spermatogenesis efficiency, may under pathological conditions (ROS excess) be responsible for structural, metabolic, and functional disorders of the male germ cells (de Lamirande and Gagnon, 1995; Griveau and Le Lannou, 1997; Aitken, 1999). This destructive effect of oxidative stress on male gametes is mainly associated with the peroxidative processes of sperm membrane components and DNA fragmentation (Twigg et al, 1998; Comhaire et al, 1999; Fraczek and Kurpisz, 2005; Aitken and Baker, 2006). However, the peroxidation of sperm membrane lipids is generally considered as the first marking point of germ cell damage induced by reactive oxygen intermediates, which in turn may lead to sperm dysfunction that results in the inability of sperm to penetrate the oocyte (Aitken and Fisher, 1994; Aitken, 1995; Sanocka and Kurpisz, 2004).
The ROS overproduction associated with inflammatory reactions may be primarily caused by pathological bacterial strains that colonize or infect the reproductive tract (Keck et al, 1998, Potts et al, 2000). The present review attempts to summarize the current state of knowledge on particular inflammatory mediators during male urogenital bacterial infections and their involvement in the origin and the degree of the oxidative stress that has serious consequences for sperm function.
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Kinetics of the Inflammatory Process |
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TopAbstractKinetics of the Inflammatory...BacteriaLeukocytesProinflammatory CytokinesConclusionsReferences |
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Bacteria |
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TopAbstractKinetics of the Inflammatory...BacteriaLeukocytesProinflammatory CytokinesConclusionsReferences |
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To date, there have been relatively few studies dedicated to the influence of particular groups and specific microbial species on sperm quality and/or their relationship with oxidative stress. The presence of infection in the male genitourinary tract has been correlated with a decrease in the number of sperm with good morphology (Menkveld and Kruger, 1998). Diemer and coworkers (Diemer et al, 2003b) have demonstrated the influence of E coli on sperm motility; incubation with leukocytes alone did not influence sperm motility, while coincubation of spermatozoa with leukocytes and E coli, significatly lowered their progressive movement in vitro. In another report, the same authors have reported that the pathogenicity of E coli is connected with its adhesive properties, which may lead to inactivation of and damage to the sperm acrosomal reaction. Electron microscopy analysis has revealed changes in sperm structure, mostly to the cell membranes of the head and midpiece but also to the internal and external acrosomal membranes (Diemer et al, 2000).
The connection between B ureolyticus and male infertility was first discussed over a decade ago. It was suggested that bacteria themselves or their toxins might affect sperm morphology (the prevalence of harmful changes to the tail was noted), increase the number of epithelial cells in the ejaculate, and diminish the levels of semen fructose, indicating specific colonization of seminal vesicles by these bacteria (Balmelli et al, 1994). Many studies have indicated that free radical species mediate the cytotoxic effects of these bacteria towards the male gametes as a consequence of peroxidative damage to the membrane structures.
Infections with U urealyticum are often considered as causes of male infertility (Shang et al, 1999; Potts et al, 2000; Han et al, 2003). The strong adhesive properties of these microbes, especially to the head of the postacrosomal region and midpiece, result in increased numbers of sperm with residual cytoplasm around the neck. The observed agglutination of sperm in the presence of mycoplasma may be related to diminished cell motility (Nunez-Calonge et al, 1998). The most toxic agents for spermatozoa are the metabolic products of U urealyticum, which include H2O2 and ammonia (NH3). Although H2O2 is itself harmful to sperm, it is also a source of hydroxide anion (OH•), which is a highly toxic radical for cell membranes. Furthermore, Ureaplasma phospholipases A and C may influence changes in the lipid composition of the cell membranes of male gametes, leading to loss of integrity and increased permeability.
The prevalent view is that bacterial invasion is associated with leukocytospermia in semen (Fedder, 1996; Depuydt et al, 1998; Ochsendorf, 1999). Bacteria may also be implicated in asymptomatic leukocytospermia in infertile individuals (Esfandiari et al, 2002). On the other hand, the lack of leukocytospermia in semen does not preclude the onset of infection (Potts et al, 2000). The bacteria themselves or their products may contribute to ROS overproduction (Wang et al, 1997; Urata et al, 2001). Some researchers have observed higher levels of ROS in the semen of patients with positive microbial cultures (Mazzilli et al, 1994). The first detectable effects of the destructive influence of ROS overproduction in ejaculates during infection are visible as changes in the sperm membranes. In our latest report, we have shown a close association between the level of sperm membrane lipid peroxidation caused by bacterial infection and the decreased fertilization capacity of spermatozoa under in vitro conditions (Jedrzejczak et al, 2005). Although defects in the sperm membranes after earlier antibiotic treatment were not manifested in standard semen analysis, they clearly limited the fertilization potential of the spermatozoa. This indicates that even when an anti-inflammatory treatment eliminates the infectious agent and reduces the leukocyte concentration in seminal plasma it does not restore the semen redox balance, as revealed by a subsequent IVF procedure (Jedrzejczak et al, 2005).
In analyzing the influence of bacterial infection on the male reproductive tract, one should also take into consideration the induction of apoptosis. In somatic cells, the mechanism of apoptosis induced by bacteria depends on the type of pathogen and probably occurs through the activation of proapoptotic proteins, inactivation of antiapoptotic proteins or the improper adjustment of the receptor-ligand system located on the infected cell surface (Chen and Zychlinsky, 1994; Grassme et al, 2001). Villegas et al (Villegas et al, 2005) have recently demonstrated for the first time a significant increase in the percentage of annexin V-positive spermatozoa after their in vitro incubation with leukocytes and some bacteria. We cannot exclude the possibility that direct contact of bacteria or their toxins with spermatozoa is also an initial signal for germ cell death in the absence of leukocyte-generated ROS. Taking into account the notions that apoptosis is signaled by ROS and that the inflammatory process is strictly connected with the activation of oxidative metabolism, it would be interesting to analyze the influences of particular inflammatory mediators on apoptosis in specific sperm subpopulations with different fertilizing capacities.
To summarize this part of the review, we can state that microbial pathogens are the prominent agents of the infectious process and their participation in the creation of the oxidative stress phenomenon depends on the type of pathogen that colonizes or infects the male reproductive system. We still do not know if the microorganisms act destructively towards the sperm without mediation by the cells of the immune system, thereby directly inducing oxidative stress that leads to subfertility.
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Leukocytes |
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TopAbstractKinetics of the Inflammatory...BacteriaLeukocytesProinflammatory CytokinesConclusionsReferences |
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The presence of leukocytes in semen is not pathological per se, since each ejaculate contains some leukocytes. The mean number of leukocytes in the semen of healthy men is about 17 x 104/mL of seminal plasma, which is composed of 50–60% granulocytes, 20–30% macrophages, and 2–5% T lymphocytes (Wolff and Anderson, 1988; Wolff, 1995). According to the World Health Organization (1999), a condition in which the number of leukocytes exceeds 1 x 106/mL of semen is defined as leukocytospermia, and this is considered to be the threshold value above which sperm dysfunction may occur. However, most authors agree that the determination of leukocyte counts in semen is important but not critical for the detection of infection or inflammation in the male reproductive tract (Rodin et al, 2003). Moreover, rather than the leukocyte numbers in semen, their activity levels decide the final effects of oxidative stress on spermatozoa (Kovalski et al, 1992; Sanocka et al, 2003). In addition, the presence of activated leukocytes in semen after elimination of an infectious agent may delay recovery of the normal oxidative balance in semen (Sanocka et al, 2003).
The origin of the leukocytes in semen, under physiological conditions, is difficult to explain. However, it has been assumed that under noninflammatory conditions, macrophages and lymphocytes infiltrate semen from the epididymis or rete testis, while granulocytes infiltrate mainly from the prostate and vas deferens (el-Demiry et al, 1985; Wolff, 1995). Under inflammatory conditions, WBC in the semen leak from the site of infection or inflammation. Taking into consideration the fact that the sperm is endangered by activated leukocytes (and their products) for quite a long period of time during their maturation, the greatest influences on spermatozoal function may be exerted during orchitis or epididymitis and during prostatitis. On the other hand, recent studies (Motrich et al, 2005; Motrich et al, 2006) have clearly demonstrated a close relationship between prostatitis and potential infertility even in nonbacterial prostatitis, as postulated previously (Leib et al, 1994).
There is also an ongoing controversy concerning the biological role of leukocytes in semen. Some reports have indicated the lack of any connection between the presence of leukocytes and semen quality or infertility status (el-Demiry et al, 1986; Tomlinson et al, 1992a; Tomlinson et al, 1993), and have suggested positive roles for these cells in the removal of dead or damaged spermatozoa (Tomlinson et al, 1992b). However, most authors point out the observed relationship between the increased number of leukocytes in semen and the deterioration of seminological parameters (Wolff et al, 1990; Yanushpolsky et al, 1996) or the fertilizing ability of sperm (Vogelpoel et al, 1991), which act mainly by influencing sperm motility and their potential for oocyte penetration (Maruyama et al, 1985; Kovalski et al, 1992). It seems likely that decreased sperm fertilizing ability is an early result of leukocytospermia associated with genitourinary infection. Prolonged oxidative stress may contribute to the damage of the male reproductive organ involved in the inflammatory process. In the case of the male gonad, this damage is connected with disturbances in spermatogenesis and loss of sperm function. Along this line, the greatest danger can be inflicted by the chronic inflammatory process without clinical symptoms (Wolff et al, 1991).
The influence of WBCs on semen function depends on the dominating leukocyte subtypes and the intensity of inflammation. Individual susceptibility to infection and extent of tissue injury are also relevant factors (Wolff, 1995; Fedder, 1996). Irrespective of the different views on the source and the number of leukocytes in semen, most authors agree that leukocytes decrease the fertilizing potential of spermatozoa, mainly by inducing additional ROS release and the secretion of numerous active biological substances, such as proteases and proinflammatory cytokines, which then participate in and intensify the inflammatory process.
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Proinflammatory Cytokines |
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TopAbstractKinetics of the Inflammatory...BacteriaLeukocytesProinflammatory CytokinesConclusionsReferences |
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)
(Feldmann and Saklatvala,
2001) (Table).
Proinflammatory cytokines usually act locally, since they are produced by
locally activated cells or produced temporarily after the stimulus has been
activated. In the male gonad, cytokines are also produced physiologically and
are involved in the normal function of the organ
(Hales et al, 1999;
Soder et al, 2000;
Diemer et al, 2003a). In this
respect, they appear as the natural components of seminal plasma
(Maegawa et al, 2002).
Moreover, some cytokines act as regulators of the physiological levels of ROS
in seminal plasma (Buch et al,
1994; Depuydt et al,
1996). The main source of cytokines in the male gonad is
testicular macrophages, although some cytokines (IL-1 and IL-6) are also
produced by the cells of rete testis, which include the Leydig and Sertoli
cells (Cudicini et al, 1997).
The participation of some cytokines in the regulation of fertility is
dependent upon their concentration. For instance, the IL-12 level correlates
with the density and morphology of sperm cells, which suggests a certain
biological role for IL-12 in male infertility
(Naz and Evans, 1998). In
turn, using human recombinant IL-6, capacitation and acrosomal reaction of
sperm can be induced and the proportion of penetrated oocytes is increased
(xenogeneic test of human sperm-hamster oocyte penetration)
(Naz and Kaplan, 1994b). On
the other hand, increased IL-6 levels have been observed in the seminal plasma
of infertile males (Naz and Kaplan,
1994a). High levels of certain cytokines in semen are often linked
with a decrease in the quality of the seminological parameters
(Gruschwitz et al, 1996). The
same cytokines that act as elements of immunomodulation for the male gonad
appear in large concentrations in semen during infection and when the tissues
are damaged. Their participation in inflammation is closely connected with the
accompanying leukocytospermia (Shimoya et
al, 1993; Depuydt et al,
1996; Comphaire et al,
1999).
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Some authors have suggested that particular cytokines modulate the
expression of genes responsible for the redox system in semen
(Shimoya et al, 1993;
Naz and Kaplan, 1994a). For
instance, an increase in ROS production by human sperm was observed after the
addition of IL-1, IL-1ß or TNF-, the result of which was an
increase in sperm membrane lipid peroxidation, as measured by the MDA level
(Buch et al, 1994). However,
many studies have demonstrated the cooperativity of proinflammatory cytokines
with other inflammatory mediators to generate toxic effects at the reaction
site (Das, 1991;
Rajasekaran et al, 1995).
Zalata and coworkers (Zalata et al,
1995) have documented an increase in lipid peroxidation after an
in vitro incubation of sperm with PMA-stimulated leukocytes, which suggests a
decrease in the biological value of sperm cell membranes in the environment of
oxidative stress. This type of observation argues in favor of the hypothesis
that interleukins do not act separately but in connection with other mediators
of the inflammatory process (Wolff,
1995). It seems likely that leukocytes mediate the induction of
ROS generation by proinflammatory cytokines. In addition, it cannot be
excluded that the oxidative stress that appears in leukocytospermia is exerted
by the increased levels of the cytokines themselves
(Rajasekaran et al, 1995). In
this situation, ROS (generated by leukocytes) acts synergistically with
proinflammatory cytokines to exacerbate the destructive environment for the
spermatozoa.
IL-1ß is a well-known proinflammatory cytokine that is especially important for testicular physiology. It is involved in autocrine and paracrine regulation of local control of spermatogenesis and spermiogenesis, and constitutes one of the elements of immune privilege in the testis (Huleihel et al, 2000; Soder et al, 2000; Fiszer et al, 2003; Rozwadowska et al, 2005). This cytokine is responsible for the development and maintenance of the immune and inflammatory responses to invading pathogens. An increase in IL-1ß expression in the testis during local infection or inflammation is associated with decreased testosterone production by Leydig cells and decreased intensity of spermatogenesis, probably mediated through apoptosis (Huleihel and Lunenfeld, 2004). The effect of IL-1ß on semen quality is hotly debated in the literature.
Camejo and coworkers (Camejo et al, 2001) have suggested a relationship between the IL-6 level in semen plasma and the intensity of sperm membrane peroxidation. IL-6 is principally produced by monocytes/macrophages and its most important functions include the stimulation of B-lymphocyte differentiation, the activation of T lymphocytes, and the stimulation of acute phase protein release. High levels of IL-6 and/or MDA in the seminal plasma of infertile males have been reported (Camejo et al, 2001; Furuya et al, 2003). The chemotactic properties of IL-8 cause an influx of leukocytes into the site of inflammation and enhanced production of ROS, which most likely are connected with its harmful influence on sperm cell membranes. The high levels of IL-6 or IL-8 present during persistent inflammation augment the peroxidation process and affect sperm function, with subsequent development of infertility. We support the view put forward by several authors that the elevated levels of IL-6 or IL-8 in seminal plasma can be sensitive markers of the early phase of the inflammatory process in the male genitourinary tract, which can be used to initiate appropriate anti-inflammatory treatment (Depuydt et al, 1996; Eggert-Krusse et al, 2001; Sanocka et al, 2003).
Another proinflammatory cytokine that may be harmful towards sperm is
TNF-. Buch and coworkers (Buch et
al, 1994) have reported increased MDA levels in semen after
incubation with recombinant TNF-. TNF-, which is one of the
major cytokines produced during inflammation, is secreted predominantly by
monocytes and macrophages, mainly after contact with lipopolysaccharide (LPS).
The cytotoxic influence of TNF- is augmented by ROS and phospholipase
A2. It is possible that the toxicity of TNF- for the sperm
membranes is increased when other cytokines are present (unpublished
data).
IL-12 has been detected in seminal plasma samples from both fertile and infertile males. The higher IL-12 levels observed in the seminal plasma samples of fertile males compared to infertile ones suggests the participation of this cytokine in the physiological functioning of the reproductive system (Naz and Evans, 1998). However, harmful effects of IL-12, such as through the induction of IL-18, on sperm cannot be excluded.
IL-18 belongs to the large IL-1 superfamily, and although it is
structurally similar to IL-1 family members, it differs in terms of mode of
action. It is not only produced by the cells of the immune system, such as
monocytes and macrophages, in response to the LPS, but can also be released
from keratinocytes, most epithelial cells, and osteoblasts
(Dinarello, 1999). The
proinflammatory activity of IL-18 is mostly linked to the stimulation of
proliferation and the cytotoxicity of natural killer (NK) cells and T
lymphocytes, among others, through the induction of IFN-
production.
IL-18 is augmented by IL-12 (Munder et al,
1998). In turn, IFN-, which is induced by both IL-18 and
IL-12, stimulates macrophages to produce TNF-, NO•, and ROS as
part of the defense against infectious agents
(Dinarello, 1999;
Nakanishi et al,
2001).
A pathological role for IL-18 has been postulated
(Fassbender et al, 1999;
Tsutsui et al, 2000;
Matsui et al, 2003;
Maerten et al, 2004). The
overproduction of this proinflammatory cytokine, particularly in combination
with IL-12, may be dangerous both to the cells of the immune system as well as
to other cells and tissues of the body. IL-18 plays a role in the pathogenesis
of many other types of disease (eg, autoimmune disorders of the liver, skin,
and kidneys, and degenerative rheumatoid inflammation) through the induction
cell apoptosis. A recent report has described the participation of IL-18 in
harmful effects on semen quality in infertile men with urogenital infections.
Moreover, some authors have suggested that IL-18 in seminal plasma serves as
another diagnostic marker for male genital tract infections
(Matalliotakis et al, 2006).
Assuming that oxidative stress leads not only to an uncontrolled increase in
the concentration of reactive oxygen metabolites, but also to the failure of
both the enzymatic and nonenzymatic members of the antioxidative system, we
cannot exclude that IL-18 acts also through changes in the activities of
enzymes that protect the sperm against these damaging metabolites. A clear
relationship between increased IL-18 and decreased glutathione peroxidase
(GPx) and selenium levels in the blood serum has been noted, for example in
patients with acute pancreatitis
(Wereszczynska-Siemiatkowska et al,
2004). The assessment of membrane peroxidation and/or apoptosis in
spermatozoa could be helpful in explaining the pathological role of IL-18
during male reproductive tract infection or
inflammation.
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Conclusions |
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TopAbstractKinetics of the Inflammatory...BacteriaLeukocytesProinflammatory CytokinesConclusionsReferences |
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