Characterization of signaling pathways leading to Fas expression induced by TNF-α: pivotal role of NF-κB

TNF-α is known to induce a strong up-regulation of Fas expression in mouse Sertoli cell cultures, leading to their apoptosis triggered by effector FasL-bearing cells. These data suggest that increased Fas expression on the cell surface might be a key event in the pathogenesis of autoimmune orchitis, by inducing a leakage of the blood-tubular barrier as a consequence of Sertoli cell apoptosis. In the present paper, we have investigated the signal transduction mechanisms involved in the regulation of Fas expression induced by TNF-α in mouse Sertoli cells. We studied the role of the transcription factor NF-κB and of MAPKs in regulating Fas expression. By using Sertoli cells transfected with a NF-κB Luc reporter gene, we proved that TNF-α activates the IκB/NF-κB system. Moreover, the use of the proteasome inhibitor lactacystin led us to demonstrate that NF-κB is required for TNF-α mediated Fas expression. By using specific inhibitors for each MAPK, we confirmed the pivotal role of the IκB/NF-κB system by demonstrating that ERKs, p38, and JNK are not involved in Fas up-regulation by TNF-α. The comprehension of these pathways could be relevant to the knowledge of the pathogenesis of autoimmune disorders in immune privileged districts of the body.