The interplay of collagen IV, tumor necrosis factor-α, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis
Siu,Michelle K.Y.; Lee,William M.; Cheng,Chuen-yan
Endocrinology 144(1): 371-387
Publication date: 2003
During spermatogenesis, preleptotene and leptotene spermatocytesmust translocate across the blood-testis barrier formed by inter-Sertolicell-tight junctions (TJs) from the basal compartment of theseminiferous epithelium adjacent to the basement membrane tothe adluminal compartment at stages VIII-IX for furtherdevelopment. Because of the close proximity between extracellularmatrix (ECM) that constitutes the basement membrane and theblood-testis barrier, we sought to investigate the role of ECMin Sertoli cell TJ dynamics. When Sertoli cells were culturedin vitro to initiate the assembly of the Sertoli cell TJ-permeabilitybarrier, the presence of an anticollagen IV antibody indeedperturbed the barrier. Because ECM is known to maintain a poolof cytokines and TNF has been shown to regulate TJ dynamicsin other epithelia, we investigated whether TNF can regulateSertoli cell TJ function via its effects on collagen 3(IV) andother proteins that maintain the homeostasis of ECM. As expected,recombinant TNF perturbed the Sertoli cell TJ-barrier assemblyin vitro dose dependently. TNF also inhibited the timely inductionof occludin, which is known to associate with the Sertoli cellTJ-barrier assembly. Furthermore, TNF induced the expressionof Sertoli cell collagen 3(IV), gelatinase B (matrix metalloprotease-9,MMP-9) and tissue inhibitor of metalloproteases-1 but not gelatinaseA (matrix metalloprotease-2), and promoted the activation ofpro-MMP-9. These results thus suggest that the activated MMP-9induced by TNF is used to cleave the existing collagen networkin the ECM, thereby perturbing the TJ-barrier. This in turncreates a negative feedback that causes TNF to induce collagen3(IV) and tissue inhibitor of metalloproteases-1 expressionso as to replenish the collagen network in the disrupted TJ-barrierand limit the activity of MMP-9. Taken collectively, these observationsstrengthen the notion that ECM is involved in the regulationof junction dynamics in addition to its structural role in thetestis.