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

• Published in: The FASEB journal 2005-03, Vol.19 (3), p.1-31
• Main Authors: Starace, Donatella, Riccioli, Anna, D'Alessio, Alessio, Giampietri, Claudia, Petrungaro, Simonetta, Galli, Roberta, Filippini, Antonio, Ziparo, Elio, De Cesaris, Paola
• Format: Article
• Language: English
• Subjects: apoptosis; MAPK; sertoli cell
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.04-2726fje

ABSTRACT 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.