Up-regulation of mitochondrial peripheral benzodiazepine receptor expression by tumor necrosis factor alpha in testicular leydig cells. Possible involvement in cell survival.
Porcine Leydig cells in primary cultures are resistant to tumor necrosis factor alpha (TNFalpha) cytotoxicity. Here we report that these cells can be rendered sensitive to TNFalpha killing by treatment with the translational inhibitor cycloheximide, suggesting the existence of proteins that can suppress the death stimulus induced by the cytokine. In search of these cytoprotective proteins, we focused on the constituents of the mitochondrial permeability transition pore (PT pore), whose opening has been shown to play a critical role in the TNFalpha-mediated death pathway. We found that TNFalpha up-regulated mRNA and protein expression of the mitochondrial peripheral benzodiazepine receptor (PBR), an outer membrane-derived constituent of the pore. A strong correlation was established between the resistance of the cells to TNFalpha killing and the density of PBR-binding sites. Concomitantly, TNFalpha down-regulated Bcl-2 mRNA and protein expression. As Bcl-2 has been shown to be an endogenous inhibitor of the PT pore, we hypothesize that the TNFalpha-induced up-regulation of PBR expression may compensate for the decrease in Bcl-2 levels to prevent the opening of the PT pore.
Rey
C
C
INSERM U. 189, Faculté de Médecine Lyon-Sud, BP12, 69921 cedex, Oullins, France.
Mauduit
C
C
Naureils
O
O
Benahmed
M
M
Louisot
P
P
Gasnier
F
F
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics; D013552:Swine; D013737:Testis / Q000166:cytology / Q000187:drug effects; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D007546:Isoquinolines; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D003513:Cycloheximide; C037850:PK 11195