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From the Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
| Correspondence to: Dr Maciej Kurpisz, Professor, Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland (e-mail: kurpimac{at}man.poznan.pl). |
| Received for publication May 11, 2007; accepted for publication August 15, 2007. |
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Abstract |
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), used singly or in combinations, were
analyzed. WBCs were isolated from the whole heparinized blood using a density
gradient technique (Histopaque 1.077). Spermatozoa were isolated from semen
samples with normal sperm parameters by both the swim-up technique (swim-up
fraction) and by a discontinuous Percoll gradient centrifugation (90% and 47%
Percoll fractions). Peroxidative damage to sperm membrane lipids was assessed
by determining the concentration of malondialdehyde (MDA) in lysates of
spermatozoa using high-performance liquid chromatography (HPLC). There were no
statistically significant differences in MDA concentrations between sperm
fractions incubated with cytokines and respective controls (spermatozoa
alone). In spermatozoa isolated by the swim-up technique, the MDA level was
significantly higher only after incubation with IL-6 and IL-8 plus WBCs when
compared to sperm incubated with leukocytes alone (0.62 ± 0.21
µmol/L and 0.42 ± 0.22 µmol/L, respectively; P <
.05). In spermatozoa recovered from the 47% Percoll, only a combination of
IL-12 and IL-18 used together with WBCs was linked with a significant increase
in MDA concentration (from 0.41 ± 0.13 µmol/L to 0.65 ± 0.19
µmol/L; P < .05). The results obtained suggest that cytokines
produced during the inflammatory process intensify the level of oxidative
stress caused by leukocytes, which may have serious consequences for sperm
membrane integrity.
Key words: Semen inflammation, peroxidative damage
Proinflammatory cytokines are the natural components of seminal plasma (Maegawa et al, 2002). In numerous reports, proinflammatory cytokines were found to regulate a physiologic function of the male gonad and to act as testicular immunomodulatory elements (Hales et al, 1999; Soder et al, 2000; Rozwadowska et al, 2005). Most of them are also involved in the fertilization process (Naz and Evans, 1998; Diemer et al, 2003; Huleihel and Lunenfeld, 2004). On the other hand, the same cytokines have been linked with a decrease in semen quality of infertile men, particularly those with urogenital tract infections (Naz and Kaplan, 1994; Gruschwitz et al, 1996; Eggert-Kruse et al, 2001; Kocak et al, 2002; Friebe et al, 2003; Paulis et al, 2003). In our earlier study, we demonstrated that cytokines deepen oxidative stress, not only by the intensification of the inflammatory process but by a direct influence on pro-oxidative and antioxidative system components as well (Sanocka et al, 2003). The oxidative stress with its consequences for sperm membranes can lead to a damage of sperm biologic function, in spite of the fact that semen consists of spermatozoa subpopulations with different fertilizing potential.
As clinical significance of selected proinflammatory cytokines and their
influence on male fertility reduction is poorly documented, we decided to
assess an in vitro effect of various cytokines (pathologic concentrations)
taking part in the inflammatory process on peroxidation of sperm membrane
lipids. Six recombinant proinflammatory cytokines, such as interleukin-1β
(IL-1β), IL-6, IL-8, IL-12, IL-18, and tumor necrosis factor alpha
(TNF-), were chosen for the study. They were used singly or in
combinations according to natural interactions taking place during the
inflammatory process, which some investigators have already observed in semen
(Depuydt et al, 1996;
Kocak et al, 2002;
Sanocka et al, 2003).
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Materials and Methods |
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were obtained from Sigma (St. Louis, MO). IL-18 was purchased from
MBL Co. Ltd. (Nagoya, Japan).
Preparation of White Blood Cell (WBC) Suspensions
Specimens of heparinized venous blood were collected from 10 healthy adults
donating to the Regional Blood Center, Pozna
, Poland. The WBCs were
isolated by a density gradient centrifugation technique using Histopaque 1.077
(Sigma). The gradients were centrifuged at 400 x g for 20
minutes at room temperature. The WBCs were harvested from buffy coats. After
two washes in Hanks' balanced salt solution (HBSS) supplemented with 0.5%
lactoalbumin hydrolyzate and sodium bicarbonate (Biokom, Lublin, Poland), the
cell pellets were resuspended in 0.83% NH4Cl-Tris, pH 7.4, and
incubated for 15 minutes at room temperature in order to lyse the
contaminating erythrocytes. The cell suspensions were centrifuged at 250
x g for 10 minutes and washed twice in phosphate-buffered
saline (PBS), pH 7.4. Cells were counted and checked for the viability by 1%
trypan blue staining. The WBC suspensions were then adjusted with PBS to a
concentration of 1 x 107 cells/ml.
Semen Preparation
Semen samples were obtained from 10 healthy volunteers with no sperm
abnormalities attending the Outpatient Clinic for Andrology (Poznan, Poland)
after 4 days of sexual abstinence. The specimens were allowed to liquefy for
30 minutes at room temperature. An aliquot of each semen specimen was
subjected to routine semen analysis in accordance with the guidelines
published by the World Health Organization
(WHO, 1999). Data recorded
included semen volume, viscosity, pH, sperm count, motility, morphology, and
viability. Sperm concentration and motility were determined using a Makler
counting chamber. Sperm viability was assessed using 1% eosin Y solution.
Sperm morphology was evaluated after Papanicolaou staining and was scored
according to Kruger's strict criteria
(Kruger et al, 1986). Each
semen specimen was tested for the presence of leukocytes by the Endtz test
(Endtz, 1974). All tested
samples were subjected to microbiologic analysis. In addition, semen samples
were checked for the presence of antisperm antibodies using direct immunobead
test (DIBT; Irvine Scientific, Santa Ana, Calif). Only semen samples from
healthy volunteers with sperm concentrations >20 x 106/mL
of semen, sperm progressive motility (A + B category) >50%, sperm
morphology >14%, absence of antisperm antibodies, leukocyte concentrations
<1 x 106/mL of semen, and bacteria concentration <1
x 103/mL of semen were used for further experiments.
Semen samples were then divided into two aliquots. The first aliquot was
used for spermatozoa separation by swim-up technique incubating of fresh semen
samples for 1 hour at 37°C in F10 (Ham's) solution supplemented with
L-glutamine and sodium bicarbonate (Biokom). From the second
aliquot, spermatozoa were isolated by a double-step discontinuous Percoll
gradient (47% and 90%; Sigma), centrifuging at 450 x g for 30
minutes at room temperature. The seminal plasma was then discarded, and
spermatozoa were harvested from the 90% Percoll and 47% Percoll fractions. The
cells from all three sperm fractions were then washed twice in PBS and finally
adjusted to a density of 1 x 107 spermatozoa/mL in PBS.
Samples containing 1 x 106 spermatozoa (the pool of two
volunteers' semen samples) from each fraction were incubated with recombinant
cytokines and/or WBCs for 1 hour at 37°C. WBCs (the pool of two donors'
blood samples) were added at a concentration of 1 x 106 cells
per milliliter of co-incubated mixture. Cytokines were added at pathologic
concentrations of 50 pg, 200 pg, 500 pg, 50 pg, 500 pg, and 50 pg per
milliliter of co-incubated cell suspension, respectively, for IL-1β,
IL-6, IL-8, IL-12, IL-18, and TNF-. The concentrations of IL-1β,
IL-6, IL-8, and TNF- were chosen according to our earlier observations
regarding infertile patients with genital tract infection/inflammation
(Sanocka et al, 2003;
Sanocka et al, 2004). As for
the concentrations of IL-12 and IL-18, they were chosen according to the other
relevant reports (Nakanishi et al,
2001; Matalliotakis et al,
2006). These co-incubated cell suspensions were next selectively
depleted to obtain pure sperm samples for membrane lipid peroxidation
assay.
Depletion of WBCs
WBCs were removed from the reaction mixture using a Dynal MPC-1
immunomagnetic cell isolation system (Dynal, Oslo, Norway). During 20 minutes
of incubation at 4°C, CD45+ cells were adsorbed onto magnetic
M-450 Dynabeads (Dynal, Oslo, Norway). Spermatozoa then were eluted in a
magnetic field at 4°C. The eluates were collected, washed, and resuspended
in PBS for a final concentration of 1 x 106 sperm/mL. Sperm
pellets were lysed with isotonic 10 mmol/L potassium buffer phosphate, pH 7.2,
and stored at –20°C until they were used for malondialdehyde (MDA)
measurement.
Determination of MDA
The lipid peroxidation was measured on the basis of MDA amounts produced in
different sperm fractions incubated together with cytokines and/or WBCs. MDA
levels were determined by a high-performance liquid chromatography (HPLC)
technique in a Waters HPLC system (Waters, Milford, MA;
Nielsen et al, 1997). Each 1
ml of sample contained: 100 µl sperm lysate; water (for a blank sample) or
the known MDA concentration; 700 µl of 1% orthophosphoric acid; and 200
µl of 42 mmol/L 2-thiobarbituric acid (TBA) in 0.1 mol HCl. The samples
were heated in a water bath for 1 hour at 100°C. After cooling, the
samples were mixed with 2 mol/L NaOH/methanol (1:12, v/v) and centrifuged for
3 minutes at 13 000 x g. Fifty-microliter aliquots of
supernatant were injected onto the LiChroCART 250-4 column packed with 5 µm
LiChrospher 100 RP-18 (Merck, Darmstadt, Germany). Each sample was run in
duplicate. Water served as a blank sample. The samples were eluted for 8
minutes at a flow rate of 0.5 ml/min using a 3:2 (v/v) mixture of 10 mol/L
KH2PO4 (pH 6.8) and methanol. The absorbance of the
eluate at 532 nm was determined using an ultraviolet detector. MDA
concentration was calculated from the area of the peak at 6.8 minutes using a
standard curve prepared with triplicate serial dilutions of freshly hydrolyzed
0.1 mmol/L 1,1,3,3-tetraethoxypropane (TEP; Sigma). The TEP was hydrolyzed for
1 hour at 50°C.
Statistical Analysis
All statistical calculations were performed using the STATISTICA software
package, 6.0 version (StatSoft, Tulsa, OK). The significant differences were
assessed using nonparametric (Friedman and Mann-Whitney U) tests and
were presented as median ± average deviation (AD). P < .05
was considered significant, P < .01 very significant, and
P < .001 most significant.
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Results |
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Effect of WBCs on MDA Concentration in Sperm Fractions
The Mann-Whitney test discriminated the WBC effect on MDA content depending
on the proinflammatory cytokines and sperm fractions used in the study (Table
1). Only in cases of spermatozoa obtained from the 90% Percoll fraction did
WBCs themselves induce the lipid peroxidation in the absence of cytokines, and
the effect was close to a significant levels. In the swim-up sperm fraction,
the presence of WBCs had a positive influence on the level of MDA when IL-12
or IL-18 (used individually) or when IL-6 combined with IL-8 or TNF-
was applied. In most cases, leukocytes and cytokines used together caused a
significant increase of membrane lipid peroxidation in spermatozoa from the
90% Percoll fraction in comparison to sperm incubated only with respective
cytokines. As for spermatozoa from 47% Percoll fraction, only in cases of
IL-18 and TNF- used individually or together with other cytokines did
WBCs have a statistically significant influence on MDA content.
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Discussion |
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A characteristic feature of proinflammatory cytokines is their synergistic,
additive, or antagonistic activity, due to which they can influence the
function of the target cells in vivo in a number of ways. This suggestion was
also included in the final conclusions of the paper of Martinez and coworkers,
although it was not experimentally verified
(Martinez et al, 2007). In our
study, in which we have used various combinations of cytokines, this
particular conclusion was extended an empirical level, thus adding to the
understanding of cytokines' nature during the inflammatory process in male
genitourinary tract. The levels of IL-6 and IL-8 in seminal plasma have been
often demonstrated as the factors linked with a decrease in quality of
seminologic parameters (Gruschwitz et al,
1996; Eggert-Kruse et al,
2001; Furuya et al,
2003; Sanocka et al,
2003; Kopa et al,
2005). The significant increase in the MDA level in spermatozoa
with the best seminologic parameters (swim-up sperm fraction) after their in
vitro incubation with IL-6, IL-8, and WBCs (Figure, panel B) may probably be
related to observed infertility in vivo. This was already suggested by several
authors who presented positive correlations between IL-6 or IL-8 levels and
MDA concentration in seminal plasma of infertile men
(Camejo et al, 2001;
Liu et al, 2003). Moreover,
the application of IL-6 together with IL-8 exerted a synergistic effect in
respect to their harmful influence on the sperm membranes (Figure, panel B).
Probably, the prolonged presence of high levels of IL-6 and IL-8 in semen
during the genitourinary tract inflammation can lead to persistent sperm
damage resulting from the peroxidative process. The assessment of the
proinflammatory cytokine levels in semen can be supplementary to the
evaluation of the male genital tract inflammation in vivo. Our data once again
support the need for the examination of these two cytokines as the excellent
markers that can be used to identify an early phase of the inflammatory
process in the male genitourinary system
(Depuydt et al, 1996;
Eggert-Kruse et al, 2001;
Sanocka et al,
2003).
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Many authors have recently focused on a new member of the IL-1 family,
namely, IL-18 (Dinarello,
1999; Nakanishi et al,
2001). Most of them postulated a rather pathologic role for this
cytokine in many diseases (Fassbender et
al, 1999; Tsutsui et al,
2000; Matsui et al,
2003; Ogata et al,
2004; Malaguarnera et al,
2006). Matalliotakis et al
(2006) have also emphasized
the detrimental influence of the elevated IL-18 levels on semen parameters and
suggested the presence of IL-18 as another marker for male genital tract
inflammation. In our research, IL-18 applied in combination with IL-12 was
more effective in exerting a deleterious effect of oxidative stress caused by
leukocytes on sperm membranes than either of cytokines used singly (Figure,
panel B). Thus, our results confirmed a synergism between these two cytokines
that has been previously postulated
(Munder et al, 2001). However,
views on the relationship between high levels of IL-12 and male infertility
are not coherent, and this cytokine is also known for taking part in the
normal functioning of male reproductive system
(Naz and Evans, 1998). It is
conceivable that IL-18 is mainly a mediator that may affect sperm membranes
through the induced changes in the antioxidative system of male gametes
(Wereszczynska-Siemiatkowska et al,
2004). Taking into consideration that some cytokines, such as
IL-1β, IL-18, or TNF-, participate in inflammatory reaction
through the induction of cell apoptosis, we cannot preclude a fact that
membrane peroxidation is not the only mechanism by which some proinflammatory
cytokines affect spermatozoa during the male reproductive tract
infection/inflammation.
Many authors have observed correlations between the levels of proinflammatory cytokines and the number of leukocytes in semen (Shimoya et al, 1993; Rajasekaran et al, 1995; Eggert-Kruse et al, 2001; Liu et al, 2003; Jedrzejczak et al, 2005; Kopa et al, 2005). However, there have been also reports demonstrating the elevated levels of proinflammatory cytokines in semen, regardless of the presence or absence of leukocytes (Alexander et al, 1998; Naz and Evans, 1998). The intensification of sperm cells' membrane peroxidation after their exposure to both cytokines and leukocytes observed in this study reconfirmed proof for the involvement of proinflammatory cytokines in the deepening of harmful activity of oxidative stress to spermatozoa. Moreover, during the inflammatory process, ROIs produced by leukocytes and due to proinflammatory cytokines cooperate with each other in provoking the structural sperm disorder. This is most probably connected with the changes in the activity of both enzymatic and nonenzymatic members of the semen antioxidative system. Our previous reports demonstrated a clear relationship between some proinflammatory cytokines and the pro-oxidative and anti-oxidative components of seminal plasma in patients with genital tract inflammation (Sanocka et al, 2003). Other authors also showed inducing properties of IL-6 toward mitochondrial SOD (Isoherranen et al, 1997). It may be hypothesized that high activities of proinflammatory cytokines in semen influence the intensity of oxidative stress, which may then have dangerous consequences for spermatozoa, indirectly affecting their redox profile as well as their close environment.
The present study is a continuation of our previous observations regarding inflammatory mediators in human semen, in which we used three preparations of spermatozoa differing structurally and functionally (Fraczek et al, 2004; Fraczek et al, 2007). In general, MDA concentrations observed in this study were lower in sperm from the 90% Percoll pellet when compared to the other fractions (Figure). These results are in agreement with the data presented in the other papers showing that differences in the rates of lipid peroxidation are related to sperm maturity and, presumably, sperm membrane structure (Aitken et al, 1994; Huszar and Vigue, 1994; Zalata et al, 1998) that can be also affected by gradient procedure itself (Kobayashi et al, 1991; Alvarez et al, 1993). The mediating role of leukocytes with respect to the harmful effects of secreted proinflammatory cytokines toward sperm membranes depended on the type of applied spermatozoal fraction and was the highest in spermatozoa from the 90% Percoll fraction, although in most observed cases the levels of MDA still remained lower when compared to sperm from the swim-up as well as the 47% Percoll fraction (Table 1). On the other hand, the subpopulation of spermatozoa recovered from the 90% Percoll gradient turned out to be the most susceptible to lipid peroxidative process in the presence of cytokines combined with leukocytes. These results are in agreement with our earlier report, in which we demonstrated differences in quantities of peroxidative products between sperm separated by the swim-up technique and those obtained from 90% Percoll gradient in the presence of bacterial strains (Fraczek et al, 2007). In our view, lower MDA levels observed in spermatozoa from the 90% Percoll fraction compared with the swim-up sperm fraction may originate from the gradient procedure and number of centrifugation used that can initiate shedding of peroxidative products from membranes. Thus, such manipulations cannot be a recommendation to use of any gradients for the separation of gametes aimed for assisted reproductive applications.
To conclude, the results obtained in this study clearly demonstrated that proinflammatory cytokines per se, even in pathologic concentrations, are unable to cause oxidative stress in semen to the level of membrane peroxidative damage. The assessment of sperm DNA integrity rather than membrane peroxidation in spermatozoa could provide further useful information in explaining the pathologic role of cytokines toward male gametes during male reproductive tract infection/inflammation. Because the harmful effect of cytokines on spermatozoa is closely connected to the accompanying leukocytospermia, we may also conclude that the evaluation of leukocyte concentration in semen still remains the important but insufficient approach to the diagnosis and treatment of male genital tract infection/inflammation and its particular stage or kinetics.
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