Activins, follistatin and immunoregulation in the epididymis

Abstract

Background: The interface between the epididymis and the immune system is implicated in many male reproductive pathologies. The resident immune cell populations and immune-environment within the epididymis are significantly different from the testis, which is an immune-privileged site. Moreover, the immune cell subsets and immunological responses between different regions of the epididymis vary considerably. The cauda epididymis is more susceptible to autoimmune responses than the caput in rodent models of active immunization or suppressed immune tolerance, and in men with congenital or physical damage to the reproductive tract. Activins are members of the transforming growth factor-b family of cytokines that are crucial for testis and epididymal development; however, they also have complex immunoregulatory properties and may play an essential role in the regulation of immunity in the reproductive tract. Materials and methods: Our recent research and relevant publications by other researchers identified following a PubMed search are reviewed. Results: The caput epididymis displays elevated endogenous expression of activins A and B and the immunoregulatory gene, indoleamine-2,3-dioxygenase, co-existing with an extensive population of intra-epithelial and interstitial macrophages and dendritic cells, which appear to be involved in regulating tolerance against sperm antigens. The caput is also relatively resistant to inflammatory damage caused by autoimmunity or bacterial infection, but the cauda, which exhibits low activin expression and high levels of the activin-binding protein, follistatin, is highly susceptible to inflammatory damage. Paradoxically, inflammation in the cauda induces increased activin production, and inhibition of activin activity reduces inflammatory responses. Studies using mouse models with altered levels of activins and follistatin indicate a relationship between the activins and genes involved in inflammation and immunoregulation. Conclusion: The existing data indicate that activins play a complex role in controlling inflammation and immunity in the epididymis and vas deferens.

The Involvement of the Chemokine RANTES in Regulating Luminal Acidification in Rat Epididymis

“…In the epididymis, macrophages are widely distributed in different segments, exhibiting unique phenotypes and function to establish and maintain an appropriate environment for sperm maturation and storage (18,38,39). Epididymal macrophages can be divided into two subsets according to their distinguished appearances.…”

Differential Immune Response to Infection and Acute Inflammation Along the Epididymis

“…It needs to be noted though that other defensins such as Defb 1, 2, and 9 are expressed at much higher levels in the cauda. This indicates a complex multitude of mechanisms that contribute to the maintenance of peripheral tolerance, whilst simultaneously providing sufficient resistance to bacteria-induced damage [reviewed in ( 54 )], it is not clear to what extend their differential distribution contributes to immune tolerance and a dampened immune response towards microbes preferentially in the proximal epididymis.…”

The Immune Characteristics of the Epididymis and the Immune Pathway of the Epididymitis Caused by Different Pathogens

“…Britan et al (66) reported that IDO is highly expressed in the mouse caput epididymis and is mainly secreted by the principal and apical cells. The drosophila mothers against the decapentaplegic protein 2/3/4 signaling pathway activated by activin A, and could regulate the expression of IDO, suggesting that activin A may be an activator of IDO expression in the mouse proximal epididymis (67). Moreover, these immune regulators may induce a tolerogenic circumstance in DCs and T cells (67,68).…”

“…The drosophila mothers against the decapentaplegic protein 2/3/4 signaling pathway activated by activin A, and could regulate the expression of IDO, suggesting that activin A may be an activator of IDO expression in the mouse proximal epididymis (67). Moreover, these immune regulators may induce a tolerogenic circumstance in DCs and T cells (67,68). Jrad-Lamine et al (69) have shown that pro-inflammatory cytokine expression is increased in the caput epididymitis of IDO-deficient mice.…”

“…Activin A, a member of the TGF-β superfamily, is an important regulator of testicular and epididymal development and function, as well as inflammation and immunity (67). In the adult murine reproductive tract, activin A mRNA levels are highest in the caput epididymis and decrease progressively toward the distal vas deferens (80,81).…”