Characterization of signaling pathways leading to Fas expression induced by TNF-alpha: pivotal role of NF-kappaB.
TNF-alpha 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-alpha in mouse Sertoli cells. We studied the role of the transcription factor NF-kappaB and of MAPKs in regulating Fas expression. By using Sertoli cells transfected with a NF-kappaB Luc reporter gene, we proved that TNF-alpha activates the IkappaB/NF-kappaB system. Moreover, the use of the proteasome inhibitor lactacystin led us to demonstrate that NF-kappaB is required for TNF-alpha mediated Fas expression. By using specific inhibitors for each MAPK, we confirmed the pivotal role of the IkappaB/NF-kappaB system by demonstrating that ERKs, p38, and JNK are not involved in Fas up-regulation by TNF-alpha. The comprehension of these pathways could be relevant to the knowledge of the pathogenesis of autoimmune disorders in immune privileged districts of the body.
Starace
Donatella
D
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Histology and Medical Embryology, University of Rome La Sapienza, Rome, Italy.
Riccioli
Anna
A
D'Alessio
Alessio
A
Giampietri
Claudia
C
Petrungaro
Simonetta
S
Galli
Roberta
R
Filippini
Antonio
A
Ziparo
Elio
E
De Cesaris
Paola
P
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects*; D020672:I-kappa B Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008156:Luciferases / Q000235:genetics; D048670:MAP Kinase Kinase 4; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D012708:Sertoli Cells / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C067713:lactacystin; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D000111:Acetylcysteine