Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Melbourne, Australia.
Department of Molecular and Translational Sciences, School of Clinical Sciences, Monash University, Clayton, Melbourne, Australia.
Andrology. 2024 Jul;12(5):964-972. doi: 10.1111/andr.13523. Epub 2023 Aug 29.
The activins (A and B) and their binding protein, follistatin, play crucial roles in development, immunoregulation and inflammation throughout the body. In the male reproductive tract of the mouse, activin A and B production is largely confined to the initial segment and proximal caput of the epididymis and the efferent ducts, under normal conditions, with very low expression in the corpus, cauda and vas deferens. However, activin A protein is present throughout the epididymis and vas deferens and is largely associated with the epithelium and interstitial macrophages. Conversely, the activin-binding protein follistatin is produced in the distal epididymis, with very high expression in the vas deferens. Activin activity in the distal tract is inhibited by follistatin, and the activin-follistatin balance is important for regulating coiling of the duct during epididymal development. In further experiments, as described in this report, in situ hybridisation was used to localise activin A mRNA principally to cells in the periductal zone and interstitium in the efferent ducts and proximal caput. Activin B mRNA, on the other hand, was localised to periductal cells in the efferent ducts and proximal epididymis and, most notably, to epithelial cells in the initial segment. Activin A is implicated in the regulation of mononuclear phagocyte function and immune responses in the caput and stimulates the expression of the key immunoregulatory protein, indoleamine 2,3-dioxygenase in this region. Activin A production in the corpus and cauda increases dramatically during bacterial epididymitis in mice, promoting inflammation and fibrosis and causing damage to the epithelium and obstruction of the epididymal duct. Consequently, it appears that the activin-follistatin axis is crucial for maintaining normal epididymal structure and function, but disruption of this balance during inflammation has deleterious effects on male fertility. Follistatin has therapeutic potential in ameliorating the proinflammatory and profibrotic effects of activins.
激活素 (A 和 B) 及其结合蛋白卵泡抑素在全身的发育、免疫调节和炎症中发挥着关键作用。在雄性生殖道中，激活素 A 和 B 的产生主要局限于附睾的初始段和近头部以及输出小管，在正常情况下，在体部、尾部和输精管中表达水平很低。然而，激活素 A 蛋白存在于整个附睾和输精管中，主要与上皮细胞和间质巨噬细胞相关。相反，激活素结合蛋白卵泡抑素在远端附睾中产生，在输精管中表达水平很高。远端小管中的激活素活性受到卵泡抑素的抑制，激活素-卵泡抑素的平衡对于调节附睾发育过程中的导管卷曲很重要。在本报告中进一步描述的实验中，原位杂交用于定位激活素 A mRNA 主要存在于输出小管和近头部的管周区和间质细胞中。另一方面，激活素 B mRNA 定位于输出小管和附睾近端的管周细胞中，特别是在初始段的上皮细胞中。激活素 A 参与调节头部的单核吞噬细胞功能和免疫反应，并刺激关键免疫调节蛋白吲哚胺 2,3-双加氧酶在该区域的表达。在小鼠细菌性附睾炎期间，激活素 A 在体部和尾部的产生急剧增加，促进炎症和纤维化，并导致上皮细胞损伤和附睾管阻塞。因此，激活素-卵泡抑素轴似乎对维持正常附睾结构和功能至关重要，但在炎症过程中这种平衡的破坏对男性生育力有不利影响。卵泡抑素在减轻激活素的促炎和促纤维化作用方面具有治疗潜力。
