Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / analogs & derivatives
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Acetylcysteine / pharmacology
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Animals
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Apoptosis
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Cells, Cultured
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Cysteine Proteinase Inhibitors / pharmacology
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Gene Expression Regulation / drug effects*
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I-kappa B Proteins / metabolism
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Luciferases / genetics
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MAP Kinase Kinase 4
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Male
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Mice
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / physiology
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / physiology*
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Recombinant Fusion Proteins
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Sertoli Cells / metabolism
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Signal Transduction*
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Transfection
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Tumor Necrosis Factor-alpha / pharmacology*
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fas Receptor / genetics*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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Cysteine Proteinase Inhibitors
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Enzyme Inhibitors
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I kappa B beta protein
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I-kappa B Proteins
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NF-kappa B
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Nfkbia protein, mouse
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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fas Receptor
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lactacystin
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NF-KappaB Inhibitor alpha
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Luciferases
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Acetylcysteine