Regulation of tumor necrosis factor cytotoxicity by calcineurin

FEBS Letters

Summer, Warren R.²  Kantrow, Stephen P.²  Lancaster, Jack R.²  Jaligam, Vijayendra R.²  Gierman, Joshua L.²  Piantadosi, Claude A.¹  Zhang, Ping² 

[1] Department of Medicine, Duke University Medical Center, Durham, NC, USA;Departments of Medicine and Physiology, Louisiana State University Health Sciences Center, 1901 Perdido Street, Suite 3205, New Orleans, LA 70112, USA

关键词: Calcineurin;    Apoptosis;    Mitochondrion;    Cytochrome c;    Cyclosporin A;    FK506;   

DOI  :  10.1016/S0014-5793(00)02083-4

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Cyclosporin (CsA) inhibits mitochondrial death signaling and opposes tumor necrosis factor (TNF)-induced apoptosis in vitro. However, CsA is also a potent inhibitor of calcineurin, a phosphatase that may participate in cell death. Therefore, we tested the hypothesis that calcineurin regulates TNF cytotoxicity in rat hepatoma cells (FTO2B). TNF-treated FTO2B cells appeared apoptotic by DNA fragmentation, nuclear condensation, annexin V binding, and caspase activation. We studied two calcineurin inhibitors, CsA and FK506, and found that each potently inhibited TNF cytotoxicity. Western blot demonstrated calcineurin in FTO2B homogenates. In a model of mitochondrial permeability transition (MPT), we found that CsA prevented MPT and cytochrome c release, while FK506 inhibited neither. In summary, we present evidence that calcineurin participates in an apoptotic death pathway activated by TNF. CsA may oppose programmed cell death by inhibiting calcineurin activity and/or inhibiting mitochondrial signaling.

【 授权许可】

Unknown