Relationship Between Cytokines and Seminal Parameters

Human semen contains a variety of different cytokines and other immunological factors and their effects on semen quality and sperm function are still the subject of debate. There is increasing evidence that many of the cytokines adversely affect spermatogenesis and steroidogenesis [28]. However, there is an ongoing controversy concerning the biological role of particular cytokines in the fertilization process. A lot of studies have indicated the lack of any connection between the cytokine levels and semen quality or infertility status [53, 54, 58, 63-65]. However, a number of authors point out the observed relationship between the cytokine hypersecretion and the deterioration of semen parameters or the fertilizing ability of sperm [56, 66-78] (Table 9.1). In these studies, high levels of certain cytokines in the semen were related to the quality of semen parameters, such as sperm count, motility and morphology, or sperm-oocyte penetration rates. Also in a few in vitro studies, an inhibitory effect of some recombinant cytokines has been found in respect to sperm

Table 9.1 List of connections between various proinflammatory cytokine levels in seminal plasma and semen quality (including oxidative stress parameters) demonstrated in in vivo as well as in vitro conditions

Proinflammatory cytokine

Participation in inflammatory reaction

Consequences on semen quality

References

IL-10

Proliferation and differentiation of B cells.

I Sperm-progressive motility

[67]

chemoattraction of leukocytes to the site

t ROS, t MDA (in vitro conditions)

[111]

of inflammation, induction of neutrophils

and monocytes generation, induction of

apoptosis

IL-2

Stimulation of growth and differentiation of T,

I Sperm count, motility.

[66]

B, NK, LAK cells, monocytes, macrophages

and morphology

IL-6

Activation and differentiation of B and T cells

I Sperm count

[67, 69, 74, 76, 77]

I Progressive motility

[67, 69, 76, 77]

I Morphology

[69]

I Sperm vitality

[77]

t MDA

[136]

f Leukocyte count

[58, 69, 77]

t ROS, I TAC

[92]

IL-8

Chemoattraction of neutrophils to the site

I Sperm motility

[72]

of inflammation, activation of neutrophils

t ROS

[105]

to phagocytosis

t MDA (in vitro conditions)

[106, 137]

f Leukocyte count

[58, 72, 104-107]

IL-12

Stimulation of proliferation, activity, and

f Sperm count, f sperm morphology

[83]

cytotoxicity of T cells and NK cells

IL-18

Stimulation of proliferation, activity, and

I Sperm concentration, J, sperm

[71]

cytotoxicity of T cells and NK cells.

motility

induction of apoptosis

(continued)

Table 9.1 (continued)

Proinflammatory cytokine

Participation in inflammatory reaction

Consequences on semen quality

References

TNF-a

Induction of proliferation and differentiation

1 Sperm count

[76]

of B cells, proliferation of T cells

1 Sperm motility

[67, 73]

and NK cells, induction of apoptosis

1 Sperm motility (in vitro conditions)

[80, 160, 161]

1 Sperm morphology

[73]

1 Integrity of the sperm membrane

[160]

(in vitro conditions)

t DNA fragmentation

[160]

f DNA fragmentation (in vitro

[161]

conditions)

f ROS (in vitro conditions)

[111]

t MDA (in vitro conditions)

[111, 137]

f PS externalization

[161]

IFN-y

Leukocyte attraction, growth, maturation.

1 Sperm count, motility, morphology

[68]

and differentiation of NK and B cells

1 Sperm motility (in vitro conditions)

[79]

t MDA (in vitro conditions)

[137]

motility [79, 80] and penetration rate of human sperm to hamster oocyte [81]. However, some authors have not found a similar effect of TNF-a and IL-8 on sperm motility and the acrosome reaction [82]. In the same study, only IFN-g showed an ability to inhibit sperm motility, but this phenomenon was observed only when high concentrations of the cytokine were applied. Thus, it appears that participation of some cytokines in the regulation of fertility is dependent upon their concentrations. For instance, the IL-12 level correlates with sperm density and morphology, which suggests a certain biological role for this interleukin in male infertility [83]. However, cytokine expression is interconnected with a variety of factors, including steroid hormones. For example, an increase in IL-1b expression in the testis during local infection or inflammation is associated with decreased testosterone production by Leydig cells and decreased intensity of spermatogenesis, probably due to apoptosis [61]. The harmful effects of cytokines are normally mediated by receptor pathways active in membrane-bound and/or soluble forms [84]. Even if the levels of cytokines in seminal plasma of fertile and infertile men are similar, possibly they may differently affect their reproductive systems because the levels of cytokine inhibitors and/ or their soluble receptors may be expressed differently in fertile and infertile men [53]. Moreover, the balance of cytokines can be modulated by prostaglandins which occur in high concentrations in the semen [62] .

By nature, cytokines rarely act in isolation, but rather in a network with other cytokines. For example, the overproduction of IL-18 in combination with IL-12 may be dangerous both to the cells of the immune system and other cells and tissues of the body. The toxicity of one cytokine for the sperm structures and function is also increased when other cytokines are also present. This has been suggested by different authors who observed in vivo correlations between various cytokine levels in seminal fluid, e.g., IL-1P and TNF-a [65, 85], TNF-a and IL-2 [86], IL-6 and IL-8, IL-1P and IL-8, IL-12 and IL-18 [85], and IL-18 and IFN-g [71]. It is worth emphasizing that some of these combinations are natural interactions taking place in the inflammatory process. This synergistic effect of different cytokine combinations has been also confirmed by in vitro studies in relation to its harmful influence on sperm motility [87] or biological membranes [88] .

]n spite of multiple in vivo studies, the involvement of cytokines and other immunoregulatory factors in male infertility is still unclear. The same cytokines that act as testicular immunomodulatory elements and regulate the physiological function of the male gonad appear in large concentrations in the semen in a number of pathological conditions, including autoimmune diseases [89, 90] , spinal cord injury [91], varicocele [92], or genital tract infection/inflammation [93, 94]. Most investigators suggest that the cytokines detected in seminal plasma are associated with the incidence of leukocytospermia but are not the cause of semen abnormalities [51, 95]. The production of ROS by leukocytes or damaged spermatozoa may be one of the mechanisms by which cellular and humoral immunity could be triggered [96]. Leukocytospermia impairs sperm function by reducing semen antioxi-dant activity and causing enhanced T helper 1 switch [96] . Moreover, beneficial effects of supplemented vitamin E on cell-mediated immunity and oxidative stress have also been reported [97]. Cytokines as important mediators of the immunologic response (cell activation, proliferation, growth, differentiation, mobility) are involved in numerous physiological and pathological processes in male genital tract, which include the mediation of inflammatory responses, the reproductive functions, and the regulation of gonadal steroid production and its release [65], Although some cytokines (IL-2, IL-8) take a key role in T-cell-mediated immune responses, their participation as mediating factors between cell-mediated immunity and male infertility still seems to be controversial.

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