Regulation of tumor necrosis factor cytotoxicity by calcineurin.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Kantrow, SP; Gierman, JL; Jaligam, VR; Zhang, P; Piantadosi, CA; Summer, WR; Lancaster, JR

Published Date

  • October 20, 2000

Published In

Volume / Issue

  • 483 / 2-3

Start / End Page

  • 119 - 124

PubMed ID

  • 11042265

Pubmed Central ID

  • 11042265

International Standard Serial Number (ISSN)

  • 0014-5793

Digital Object Identifier (DOI)

  • 10.1016/s0014-5793(00)02083-4

Language

  • eng

Conference Location

  • England