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Equine July/August 2009 (Vol 4, No 6)

Abstract Thoughts — Inflammation and Male Infertility: A Break in Immune Privilege Affects "Mojo"

by David J. Hurley, PhD, James N. Moore, DVM, PhD

    Abstract

    Cytokines are regulatory proteins involved in haematopoiesis, immune cell development, inflammation and immune responses. Several cytokines have direct effects on testicular cell functions, and a number of these are produced within the testis even in the absence of inflammation or immune activation events. There is compelling evidence that cytokines, in fact, play an important regulatory role in the development and normal function of the testis. Pro-inflammatory cytokines including interleukin-1 and interleukin-6 have direct effects on spermatogenic cell differentiation and testicular steroidogenesis. Stem cell factor and leukaemia inhibitory factor, cytokines normally involved in haematopoiesis, also play a role in spermatogenesis. Anti-inflammatory cytokines of the transforming growth factor-beta family are implicated in testicular development. Consequently, local or systemic up-regulation of cytokine expression during injury, illness or infection may contribute to the disruption of testicular function and fertility that frequently accompanies these conditions. The aim of this review is to provide a very brief summary of the extensive literature dealing with cytokines in testicular biology, and to follow this with some speculation concerning the significance of these molecules in interactions between the immune system and the testis.

    Commentary

    Fertility is a full-time job. Sperm production is a nearly continuous enterprise that requires a very delicate balance of hormones and cellular interactions. Although reproductive biologists and immunologists have "declared" that testicular tissue is immune privileged, there is growing evidence that local inflammatory and immune responses to infection and tissue damage occur in the testes as they do in other body tissues. However, it has been widely observed that grafts to the testes have an extended acceptance period, suggesting that this tissue has a natural level of "immune neutrality." Clinically, it has been demonstrated that many cases of chronic infertility in humans (and likely in all other mammals) are driven by chronic inflammatory processes that result in the development of antisperm antibody"mediated autoimmunity and permanent infertility. Testicular infections or injuries have reportedly resulted in transient periods of infertility that may last for days or weeks.

    The interesting balance between active inflammatory/immune responses and the apparent dampening of inflammatory and immune activity in the testes seems to be related to two major modulations of typical immune regulation. The resident macrophages in the testes have weaker-than-normal inflammatory cytokine responses to common inflammatory triggers and produce higher-than-normal quantities of cytokines that have immune-dampening activities.1

    In contrast, monocytes, mast cells, neutrophils, and lymphocytes recruited in the presence of testicular infection or injury produce levels of cytokines, lipid mediators (e.g., prostaglandins), and regulatory peptides at levels comparable to those observed in other areas of the body. The inflammatory products produced by recruited inflammatory cells act in autocrine and paracrine modes to dampen sperm development, reduce androgen production, and increase estrogen production, all of which reduce the maturation rate of sperm and depress fertility during the days and weeks that follow these inflammatory processes.

    The article by Hedger and Meinhardt provides a clear and relatively complete review of the knowledge base concerning the cross talk between the immune system and testicular function. While this excellent review article primarily covers studies in rodents and is hesitant to extend these findings beyond their strict experimental context, it contains a lot of information that can help explain how bacterial or viral infections, or physical damage to the scrotum and testes, can produce infertile stallions. Further, it indirectly suggests that injuries or infections not directly involving the testes may initiate a cytokine-mediated "endocrine" response that may modulate the function of cells critical to sperm development or may induce enzymes that alter the androgen"estrogen balance in stallions.

    Some cytokines have a particularly interesting role in modulating male fertility. For example, interleukin (IL)-6, a cytokine that can have proinflammatory or antiinflammatory effects, depending on when it is produced and the other cytokines are expressed, increases aromatase activity in the testes of mice infected with Taenia crassiceps.2 Aromatase converts androgen into estrogen, leading to loss of sperm production and, in this infection model, to feminization of male mice. IL-6 is produced by Sertoli cells during spermatogenesis under the control of follicle-stimulating hormone (FSH), testosterone, and neuropeptides. IL-6 is an important regulator of testosterone production and, at physiologic levels, is a component of spermatogenesis. In an inflammatory situation, the effects of IL-6 and IL-1β lead to a reduction in androgen concentration that interferes with sperm production.

    IL-1 has two isoforms—IL-1α and IL-1β. IL-1β, the predominant form, is released during an inflammatory response, whereas IL-1α is primarily restricted to the cells that produce it and regulates many other functions. IL-1α is produced by Sertoli cells and acts on many cells in the cascade, leading to spermatogenesis. IL-1β inhibits the response of Sertoli cells to FSH and stimulates production of transferrin and lactate by Sertoli cells. Inflammatory IL-1β alters the function of P450 enzymes responsible for steroidogenesis from cholesterol in Leydig cells, leading to a reduction in the number of functional sperm.

    Tumor necrosis factor α (TNF-α) and FasL (expression of this cell death"associated receptor is increased by TNF-α) play a role in the survival of postmeiotic protosperm cells. TNF-α reduces Leydig cell steroidogenesis and alters patterns of apoptosis (programmed cell death) in germ cells. Working together with IL-1β, TNF-α provides a strong inhibitory signal to sperm production. TNF-α also induces the expression of FasL on Sertoli cells, marking them as targets for apoptosis. When the rate of apoptosis of Sertoli cells is excessive, it reduces the efficiency of sperm production. TNF-α also induces interferon γ (IFN-γ) production by T cells in tissue. The combination of IFN-γ and TNF-α leads to a further increase in apoptosis in many different cells within the testes and reduces the number of mature sperm produced.

    Antiinflammatory cytokines (e.g., transforming growth factor β [TGF-β], c-kit receptor, IL-10) are produced in the testes by resident macrophages. These cytokines appear to provide a strong basis for the perceived immune privilege of the testes. They dampen the inflammatory and immune responses and are produced routinely in the testes during sperm development, both by resident macrophages and by other cells that regulate sperm development.

    While the concept of immune privilege appears to be true for the testes, it does not mean that testicular damage or infection will not result in an inflammatory or immune response. Considerable evidence shows that inflammatory cells are strongly recruited to infected or damaged testicular tissue in rats and that lymphocytes, monocytes, and dendritic cells are found in variable numbers in human and rodent testes (where they have been studied).1 In addition, in vivo studies in mice and rats have shown that these recruited cells function much as they do elsewhere in the body. Further, in some experimental models, administration of exogenous cytokines (e.g., IL-1, TNF-α, IFN-γ) has induced changes in steroidogenesis, aromatase activity, and sperm maturation, suggesting that infection at a site remote from the testes that induces a strong systemic inflammatory response may also temporarily alter male fertility.

    Therefore, when inflammation is involved, the theme for testicular function may be, "There's a bad moon on the rise."3 However, if inflammation can be well managed, a stallion could whinny, "Got my mojo working."4

    *Reprinted verbatim from Hedger MP, Meinhardt A. Cytokines and the immune-testicular axis. J Reprod Immunol 2003;58(1):1-26; with permission from Elsevier.

    1. Hedger MP. Macrophages and the immune responsiveness of the testis. J Reprod Immunol 2002;
    57:19-34.

    2. Morales-Montor J, Baig S, Mitchell R, et al. Immunoendocrine interactions during chronic cysticercosis determine male mouse feminization: role of IL-6. J Immunol 2001;167:4527-4533.

    3. John Fogerty. Bad moon on the rise. Green River [album]. Fantasy Records: 1969.

    4. Preston Foster. Got my mojo working. 1956. Muddy Waters. Baton Records: 1957.

    References »

    NEXT: Clinical Snapshot — Recurrent Epistaxis in a Thoroughbred Mare

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