Tumor necrosis factor α-mediated restructuring of the Sertoli cell barrier in vitro involves matrix metalloprotease 9 (MMP9), membrane-bound intercellular adhesion molecule-1 (ICAM-1) and the actin cytoskeleton

Abstract

The mammalian blood-testis barrier (BTB) restructures throughout spermatogenesis, thereby allowing developing germ cells to enter the adluminal compartment of the seminiferous epithelium. Previous studies have shown pro-inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-1α to be important regulators of Sertoli cell barrier/BTB function in vitro and in vivo. In this study, the effects of TNFα on Sertoli cell barrier function were assessed, with emphasis on changes in proteases and cell adhesion molecules following treatment. By immunoblotting and immunohistochemistry, MMP9 was found to be present in germ cells, localizing by and large to spermatocytes and spermatids in the adult rat testis. Following treatment of Sertoli cells with physiologically relevant consecutive doses of recombinant human TNFα (25 ng/ml), the steady-state levels of active-matrix metalloprotease 9 (MMP9), membrane-bound intercellular adhesion molecule (mICAM-1) and androgen receptor increased significantly. TNFα also downregulated the steady-state level of occludin, in agreement with earlier results that showed TNFα to disrupt Sertoli cell barrier/BTB function. In addition, TNFα affected the filamentous actin cytoskeleton in Sertoli cells, which appeared to be mediated by cortactin, a regulator of actin dynamics. Taken collectively, these findings imply that germ cells may be involved in BTB restructuring via the localized production of TNFα. These results also illustrate that barrier restructuring correlated with an increase in Sertoli cell mICAM-1, suggesting that it may be critical for adhesion as germ cells traverse the “opened” BTB.

Intercellular adhesion molecule 1: Recent findings and new concepts involved in mammalian spermatogenesis

“…For instance, early studies by flow cytometry showed the presence of ICAM1 on the surface of mouse Sertoli cells [173, 174]; however, the significance of this important finding probably went unknown to investigators at the time because cell junctions in the testis were largely uncharacterized structures in the early 1990s. In recent studies, we confirmed and expanded these initial findings by illustrating ICAM1 expression in both Sertoli and germ cells [49, 175]. Immunolocalization studies revealed ICAM1 to be present in all stages of seminiferous epithelial cycle, with ICAM1 staining surrounding the heads of elongating/elongated spermatids at stages IX–XIII of the seminiferous epithelial cycle where it likely participates in cell adhesion.…”

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

“…associated with the degradation of TJPs (16,17). Therefore, we next determined if ZIKV infection could alter the expression of CAMs and MMPs in HSeCs.…”

“…This unique mechanism for the transit of spermatocytes requires a restructuring of the SCB via modulating tight junction proteins throughout spermatogenesis without compromising the homeostasis of the seminiferous tubules (9). However, cell adhesion molecules such as ICAM-1 and VCAM-1 and MMPs induced by inflammatory triggers, including TNF-␣ and IL-1␣, play a critical role in junction disruption and cell movement (16). The pattern of the ZIKV-induced response in the SCB is very similar to the WNV-BBB interaction.…”

Inhibitory Effect of Melanoma Differentiation Associated Gene-7/Interleukin-24 on Invasion In Vitro of Human Melanoma Cancer Cells

“…ICAM-1 is a member of the immunoglobulin superfamily, which is typically expressed on the surface of endothelial cells to mediate the transmigration of leukocytes into the tissues (16). In the epithelial derived carcinoma, such as melanoma, the expression of ICAM-1 is correlated to the malignancy of the diseases (17).…”