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Apoptosis

, Volume 14, Issue 3, pp 320–332 | Cite as

TNFα-induced macrophage death via caspase-dependent and independent pathways

  • Tri M. Tran
  • Vladislav Temkin
  • Bo Shi
  • Lisa Pagliari
  • Soizic Daniel
  • Christiane Ferran
  • Richard M. PopeEmail author
Original Paper

Abstract

Macrophages are the principal source of TNFα, yet they are highly resistant to TNFα-mediated cell death. Previously, employing in vitro differentiated human macrophages, we showed that following the inhibition of NF-κB, TNFα-induced caspase-8 activation contributes to DNA fragmentation but is not necessary for the loss of the inner mitochondrial transmembrane potential (ΔΨm) or cell death. We here extend these observations to demonstrate that, when NF-κB is inhibited in macrophages, TNFα alters lysosomal membrane permeability (LMP). This results in the release of cathepsin B with subsequent loss of ΔΨm and caspase-8 independent cell death. Interestingly, the cytoprotective, NF-κB-dependent protein A20 was rapidly induced in macrophages treated with TNFα. Ectopic expression of A20 in macrophages preserves LMP following treatment with TNFα, and as a result, mitochondrial integrity is safeguarded and macrophages are protected from cell death. These observations demonstrate that TNFα triggers both caspase 8-dependent and -independent cell death pathways in macrophages and identify a novel mechanism by which A20 protects these cells against both pathways.

Keywords

Apoptosis Caspase-8 Cathepsin B A20 

Notes

Acknowledgments

This work was partly funded by R01 grants from the NIH: AR049217 and AR048269 to RMP and DK063275 and HL080130 to CF.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Tri M. Tran
    • 1
  • Vladislav Temkin
    • 1
  • Bo Shi
    • 1
  • Lisa Pagliari
    • 1
  • Soizic Daniel
    • 2
  • Christiane Ferran
    • 2
  • Richard M. Pope
    • 1
    Email author
  1. 1.Division of Rheumatology, Department of MedicineNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Division of Vascular Surgery and Nephrology, Departments of Surgery and Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

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