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Programmed necrotic cell death induced by complement involves a Bid-dependent pathway

Lea Ziporen1, Natalie Donin, Taisia Shmushkovich

  • 1Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Journal of Immunology (Baltimore, Md. : 1950)
|December 26, 2008
PubMed

Insights

The membrane attack complex (MAC) triggers cell death, but Bid knockout cells show resistance. This suggests Bid plays a key role in MAC-induced cell death pathways.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • The complement system's membrane attack complex (MAC) induces necrotic cell death.
  • Bcl-2 is known to protect cells against MAC-induced necrosis.

Purpose of the Study:

  • To investigate the role of the proapoptotic protein Bid in MAC-induced cytotoxicity.
  • To understand the mechanisms by which MAC induces cell death.

Main Methods:

  • Utilized Bid knockout (Bid-/-) mouse embryonic fibroblasts (MEF) and primary fibroblasts.
  • Employed small interfering RNA (siRNA) for Bid silencing in various cell lines.
  • Analyzed complement protein deposition (C3, C9) and expression of complement inhibitors (Crry, CD59).
  • Assessed cell lysis using toxic agents and measured Bid cleavage in response to MAC.

Main Results:

  • Bid-/- fibroblasts exhibited significantly lower damage and lysis from complement compared to wild-type (WT) cells.
  • Bid silencing conferred resistance to complement-mediated lysis in mouse, K562, and Jurkat cells.
  • Bid-/- MEF showed resistance to other pore-forming toxins like streptolysin O, melittin, and A23187.
  • Less C3 and C9 deposition occurred on Bid-/- cells despite reduced complement inhibitor expression.
  • Bid cleavage was observed in WT MEF upon MAC exposure and was reduced by a pan-caspase inhibitor, correlating with reduced cell lysis.

Conclusions:

  • Complement MAC activates distinct cell death pathways.
  • One pathway involves caspases and Bid, while another is Bid-independent.
  • Bid plays a crucial role in mediating MAC-induced cytotoxicity.

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