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BCL-XL regulates TNF-alpha-mediated cell death independently of NF-kappaB, FLIP and IAPs

Raffaella Gozzelino1, Carme Sole, Nuria Llecha

  • 1Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Lleida, Spain.

Cell Research
|July 2, 2008
PubMed

Insights

Tumor necrosis factor alpha (TNF-alpha) normally does not induce apoptosis in neurons. Inhibition of macromolecular synthesis sensitizes neurons to TNF-alpha by reducing Bcl-x(L) levels, not by blocking NF-kappaB.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor necrosis factor alpha (TNF-alpha) receptor signaling can trigger apoptosis or survival pathways.
  • Inhibition of macromolecular synthesis is thought to sensitize cells to TNF-alpha-induced death via NF-kappaB transcriptional blockade, but this is unproven in the nervous system.

Purpose of the Study:

  • To investigate the mechanism by which macromolecular synthesis inhibition sensitizes neurons to TNF-alpha-induced apoptosis.
  • To identify the key molecular regulators of neuronal sensitivity to TNF-alpha.

Main Methods:

  • Treatment of PC12 cells and cortical neurons with TNF-alpha and Actinomycin D (ActD).
  • Analysis of apoptotic pathway activation (caspases, tBid).
  • Assessment of NF-kappaB target genes (IAPs, FLIP) and Bcl-2 family proteins (Bcl-x(L), Bcl-2, Bax, Bak) using Western blotting.
  • Manipulation of Bcl-x(L) levels via overexpression and RNA interference (RNAi).

Main Results:

  • TNF-alpha alone did not induce apoptosis in PC12 cells or cortical neurons.
  • ActD treatment sensitized cells to TNF-alpha-induced apoptosis, involving caspase-8, tBid, caspase-9, and caspase-3 activation.
  • ActD treatment reduced Bcl-x(L) protein levels, but not Bcl-2, Bax, or Bak.
  • Overexpression of Bcl-x(L) protected against TNF-alpha/ActD-induced cell death.
  • Downregulation of Bcl-x(L) using RNAi rendered cells sensitive to TNF-alpha-induced apoptosis without ActD.
  • Bcl-x(L) downregulation did not impact TNF-alpha-mediated NF-kappaB activation.

Conclusions:

  • Bcl-x(L) is a critical endogenous regulator of neuronal sensitivity to TNF-alpha-induced apoptosis.
  • Neuronal resistance to TNF-alpha is mediated by Bcl-x(L) in an NF-kappaB-independent manner.
  • Targeting Bcl-x(L) may offer therapeutic strategies for neurological conditions involving TNF-alpha signaling.

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