Cryptorchidism-induced CFTR down-regulation results in disruption of testicular tight junctions through up-regulation of NF-κB/COX-2/PGE2
Authors: Chen, Jing; Fok, Kin Lam; Chen, Hui; Zhang, Xiao Hu; Xu, Wen Ming; Chan, Hsiao Chang
Source: Human Reproduction, Volume 27, Number 9, 3 September 2012 , pp. 2585-2597(13)
Publisher: Oxford University Press
Does elevated temperature-induced cystic fibrosis transmembrane conductance regulator (CFTR) down-regulation in Sertoli cells in cryptorchid testis disrupt testicular tight junctions (TJs) through the nuclear factor kappa B (NF-κB)/cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway?
Our results suggest that CFTR may be involved in regulating testicular TJs and the blood-testis barrier (BTB) through its negative regulation of the NF-κB/COX-2/PGE2 pathway in Sertoli cells, a defect of which may result in the spermatogenesis defect in cryptorchidism.
WHAT IS KNOWN ALREADY
Cryptorchidism, or undescended testes, is known to result in defective spermatogenesis. Although an elevated testicular temperature is regarded as an important factor affecting spermatogenesis in cryptorchidism, the exact mechanism remains elusive. It is known that the expression of functional CFTR is temperature sensitive. Our previous study has demonstrated that CFTR negatively regulates NF-κB/COX-2/PGE2 in bronchial epithelial cells. Disruption of TJs by COX-2/PGE2 has been found in tumour cells.
STUDY DESIGN AND METHODS
Expression of CFTR, NF-κB, COX-2 and TJ proteins was examined in the testes of a surgical-induced cryptorchidism mouse model and a testicular hyperthermia mouse model, as well as in control or CFTR-inhibited/knocked down primary rat Sertoli cells. PGE2 production was measured by ELISA. Sertoli cell barrier function was determined by transepethelial resistance (TER) measurements in rat Sertoli cell primary cultures. BTB integrity in the cryptorchidism model was monitored by examining tracker dye injected into seminiferous tubules.
Down-regulation of CFTR accompanied by activation of NF-κB, up-regulation of COX-2 and down-regulation of TJ proteins, including ZO-1 and occludin, was observed in a cryptorchidism mouse model. BTB leakage revealed impaired BTB integrity in cryptorchid testes, confirming the destruction of TJs. The inverse correlation of CFTR and COX-2 was further confirmed in a mouse testis hyperthermia model and CFTR knockout mouse model. Culturing primary Sertoli cells at 37°C, which mimics the pathological condition of cryptorchidism, led to a significant decrease in CFTR and increase in COX-2 expression and PGE2 production compared with the culture at the physiological 32°C. Inhibition or knockdown of CFTR led to increased COX-2 but decreased ZO-1 and occludin expression in Sertoli cells, which could be mimicked by PGE2, but reversed by NF-κB or COX-2 inhibitor, suggesting that the regulation of TJs by CFTR is mediated by a NF-κB/COX-2/PGE2 pathway. Inhibition of CFTR or administration of PGE2 significantly decreased Sertoli cell TER.
This study has tested only the CFTR/NF-κB/COX-2/PGE2 pathway in mouse testes in vivo and in rat Sertoli cells in vitro, and thus, it has some limitations. Further investigations in other species, especially humans, are needed.
WIDER IMPLICATIONS OF THE FINDINGS
Our study may shed more light on one of the aspects of the complicated underlying mechanisms of defective spermatogenesis induced by cryptorchidism.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the National Basic Research Program of China (2012 CB944900), Natural Sciences Foundation of China (30870933), Li Ka Shing Institute of Health Sciences, the Focused Investment Scheme of the Chinese University of Hong Kong and Morningside Foundation. The authors declare no conflict of interest.
Document Type: Research Article
Publication date: 2012-09-03
- Human Reproduction features full-length, peer-reviewed papers reporting original research, clinical case histories, as well as opinions and debates on topical issues. Papers published cover the scientific and medical aspects of reproductive physiology and pathology, endocrinology, andrology, gonad function, gametogenesis, fertilization, embryo development, implantation, pregnancy, genetics, genetic diagnosis, oncology, infectious disease, surgery, contraception, infertility treatment, psychology, ethics and social issues. The highest scientific and editorial standard is maintained throughout the journal along with a rapid rate of publication.