Regulation of tumor necrosis factor cytotoxicity by calcineurin

S P Kantrow; J L Gierman; V R Jaligam; P Zhang; C A Piantadosi; W R Summer; J R Lancaster Jr

doi:10.1016/s0014-5793(00)02083-4

Regulation of tumor necrosis factor cytotoxicity by calcineurin

FEBS Lett. 2000 Oct 20;483(2-3):119-24. doi: 10.1016/s0014-5793(00)02083-4.

Authors

S P Kantrow¹, J L Gierman, V R Jaligam, P Zhang, C A Piantadosi, W R Summer, J R Lancaster Jr

Affiliation

¹ Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, 70012, USA. skantr@lsumc.edu

PMID: 11042265
DOI: 10.1016/s0014-5793(00)02083-4

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects*
Calcineurin / pharmacology*
Caspases / drug effects
Caspases / metabolism
Cell Death / drug effects
Cyclosporine / pharmacology
Cytochrome c Group / drug effects
Cytochrome c Group / metabolism
DNA Fragmentation / drug effects
DNA, Neoplasm / drug effects
DNA, Neoplasm / genetics
Dactinomycin / pharmacology
Dose-Response Relationship, Drug
Intracellular Membranes / drug effects
Intracellular Membranes / physiology
L-Lactate Dehydrogenase / drug effects
L-Lactate Dehydrogenase / metabolism
Mitochondria, Liver / drug effects
Mitochondria, Liver / metabolism
Mitochondrial Swelling / drug effects
Permeability / drug effects
Rats
Rats, Sprague-Dawley
Tacrolimus / pharmacology
Tumor Cells, Cultured / cytology
Tumor Cells, Cultured / drug effects
Tumor Cells, Cultured / metabolism
Tumor Necrosis Factor-alpha / pharmacology*

Substances

Cytochrome c Group
DNA, Neoplasm
Tumor Necrosis Factor-alpha
Dactinomycin
Cyclosporine
L-Lactate Dehydrogenase
Calcineurin
Caspases
Tacrolimus