Tumour necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor-alpha (TNF-alpha) family of cytokines which is known to induce apoptosis upon binding to its death domain-containing receptors, DR4/TRAIL-R1 and DR5/TRAIL-R2. Two additional TRAIL receptors, DcR1/TRAIL-R3 and DcR2/TRAIL-R4, lack functional death domains and act as decoy receptors for TRAIL. In this study, the presence of TRAIL and its receptors was investigated by immunohistochemistry in adult human testes. In addition, TRAIL and its receptors were studied in terms of protein and mRNA using western blot analysis and RT-PCR respectively. TRAIL and its receptors were immunodetected according to the different testicular cell types: TRAIL, DR5/TRAIL-R2 and DcR2/TRAIL-R4 were localized in Leydig cells, DR4/TRAIL-R1 was seen in peritubular and Sertoli cells whereas ligand and all receptors were detected in germ cells. Proteins and mRNA corresponding to TRAIL and its receptors were also identified in adult human testes. In conclusion, TRAIL and its receptors DR4/TRAIL-R1, DR5/TRAIL-R2, DcR1/TRAIL-R3 and DcR2/TRAIL-R4 are expressed in the human testis, and are predominantly localized in different germ cell types.
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"Although OPG has been initially identified as a member of the soluble tumor necrosis factor (TNF)-receptor family, inhibiting RANKLmediated osteoclastogenesis, several in vitro studies have shown its ability to also neutralize TRAIL (Emery et al. 1998, Miyashita et al. 2004, Zauli et al. 2009). Among different tissues, it is noteworthy that TRAIL and its receptors are abundantly expressed in human testis (Grataroli et al. 2004). Although TRAIL has been proposed to contribute to the control of the number of spermatogonia (Coureuil et al. 2010), the physiopathological role of TRAIL in testis remains to be fully elucidated. "
[Show abstract][Hide abstract] ABSTRACT: The expression of TRAIL and of its receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4) has been documented in testis, but the presence of soluble TRAIL in seminal fluid, as well as the potential physiopathological role of the TRAIL/TRAIL-R system in spermatozoa, has not been previously investigated. Male donors (n=123) belonging to couples presenting for infertility evaluation were consecutively enrolled in this study. The presence of soluble TRAIL was analyzed in seminal samples by ELISA, while the surface expression of TRAIL receptors was investigated by flow cytometry. High levels of soluble TRAIL were detected in seminal plasma (median: 11621 pg/ml; mean±SD: 13371±8367 pg/ml) and flow cytometric analysis revealed a variable expression of TRAIL receptors in the sperm cellular fraction among different subjects. In addition, the effect of physiologically relevant concentrations of recombinant TRAIL was investigated on survival and motility of spermatozoa. Of interest, the in vitro exposure of capacitated spermatozoa to recombinant TRAIL (10 ng/ml) significantly preserved their overall survival. Therefore, the present study documents for the first time the presence of elevated levels of the anti-inflammatory cytokine TRAIL in seminal fluids. Moreover, the demonstration that recombinant TRAIL promotes spermatozoa survival after capacitation suggests potential therapeutic implications.
"Tumor necrosis factor (TNF) related to apoptosis-inducing ligand (TRAIL/Apo2L/TNFSF10) is a member of the TNF super family of proteins involved in cancer development and autoimmune diseases , , and is expressed in human and rodent testis, including germ cells, Sertoli cells, and Leydig cells , , , . TRAIL is a Type II transmembrane protein that binds to either of two receptors in humans, DR4 (TRAIL-R1/TNFRSF10A) and DR5 (TRAIL-R2/TNFRSF10B) , . "
[Show abstract][Hide abstract] ABSTRACT: TRAIL (TNFSF10/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily of proteins and is expressed in human and rodent testis. Although the functional role of TRAIL in spermatogenesis is not known, TRAIL is recognized to induce apoptosis via binding to its cognate receptors; DR4 (TRAIL-R1/TNFRSF10A) and DR5 (TRAIL-R2/TNFRSF10B). Here, we utilize Trail gene-deficient (Trail-/-) mice to evaluate the role of TRAIL in spermatogenesis by measuring testis weight, germ cell apoptosis, and spermatid head count at postnatal day (PND) 28 (pubertal) and PND 56 (adult). Trail-/- mice have significantly reduced testis to body weight ratios as compared to wild-type C57BL/6J at both ages. Also, Trail-/- mice (PND 28) show a dramatic increase in basal germ cell apoptotic index (AI, 16.77) as compared to C57BL/6J (3.5). In the testis of adult C57BL/6J mice, the AI was lower than in PND 28 C57BL/6J mice (2.2). However, in adult Trail-/- mice, the AI was still higher than that of controls (9.0); indicating a relative high incidence of germ cell apoptosis. Expression of cleaved caspase-8 (CC8) and cleaved caspase-9 (CC9) (markers of the extrinsic and intrinsic apoptotic pathway, respectively) revealed a two-fold increase in the activity of both pathways in adult Trail-/- mice compared to C57BL/6J. Spermatid head counts in adult Trail-/- mice were dramatically reduced by 54% compared to C57BL/6J, indicating these animals suffer a marked decline in the production of mature spermatozoa. Taken together, these findings indicate that TRAIL is an important signaling molecule for maintaining germ cell homeostasis and functional spermatogenesis in the testis.
"Additionally, DR5 receptors were observed in Leydig cells whereas DR4 receptors were expressed in post-meiotic germ cells. In a later study, Grataroli et al. (2004) demonstrated by using immunohistochemistry that TRAIL and its receptors were expressed in different human testicular germ cell types. TRAIL and receptor DR5 as well as decoy receptors were localized in Leydig cells, whereas DR4 receptor was detected in human peritubular and Sertoli cells. "
[Show abstract][Hide abstract] ABSTRACT: The spermatozoon is a highly specialized cell, which main function is to transport the male haploid genome in the female genital
tract and to deliver it during fertilization of the oocyte. Several reports have shown that the molecular machinery involved
in apoptosis in somatic cells is also present in sperm cells during their generation in the testis as well as in the mature,
ejaculated mammalian spermatozoa. The aim of the present chapter is to give an overview of recent research on apoptosis in
male germ cells and in ejaculated spermatozoa, pointing out its regulation and potential role in important sperm functions.
The potential role that oxidative-stress and mitochondrial dysfunction could play as inductors of apoptosis in both fresh
and frozen-thawed spermatozoa will be also discussed.