Nuclear factor-kappa B activation in human testicular apoptosis

Apoptotic cell death plays an important role in limiting testicular germ cell population during spermatogenesis and its dysregulation has been shown to be associated with male infertility. The growing evidence on the role of the transcription factor nuclear factor (NF)-kappaB in controlling apoptosis prompted us to investigate NF-kappaB activity in the normal human testis and its role in testis tissue undergoing excessive apoptosis in vitro. In electrophoretic mobility shift assays, low-level constitutive NF-kappaB DNA-binding activity was found and, by immunostaining of the RelA and p50 NF-kappaB subunits, was localized to Sertoli cell nuclei. During in vitro-induced testicular apoptosis, the Sertoli cell nuclear NF-kappaB levels and whole seminiferous tubule NF-kappaB DNA-binding activity increased previous detection of germ cells undergoing apoptosis. The anti-inflammatory drug sulfasalazine effectively suppressed stress-induced NF-kappaB DNA binding and NF-kappaB-mediated IkappaBalpha gene expression. Importantly, concomitantly with inhibiting NF-kappaB, sulfasalazine blocked germ cell apoptosis. These results suggest that during testicular stress Sertoli cell NF-kappaB proteins exert proapoptotic effects on germ cells, which raises the possibility that pharmacological inhibition of NF-kappaB could be a therapeutic target in transient stress situations involving excessive germ cell death.