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Nitric oxide induces thymocyte apoptosis via a caspase-1-dependent mechanism

X Zhou1, S A Gordon, Y M Kim

  • 1Department of Surgery, University of Pittsburgh School of Medicine, and Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|July 21, 2000
PubMed

Insights

Nitric oxide (NO) triggers thymocyte apoptosis through a caspase-1-dependent pathway, not involving caspase-3. This research reveals a novel mechanism for NO-induced cell death in immune cells.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Nitric oxide (NO) is known to induce apoptosis in thymocytes via a p53-dependent pathway.
  • The specific role of caspases in NO-induced thymocyte apoptosis requires further elucidation.

Purpose of the Study:

  • To investigate the involvement of caspases in nitric oxide-induced thymocyte apoptosis.
  • To determine whether caspase-1 or caspase-3 is the primary mediator of this process.

Main Methods:

  • Dose-dependent inhibition of NO-induced apoptosis using specific caspase inhibitors (pan-caspase, caspase-1, caspase-3).
  • Assessing caspase activity and cleavage of downstream targets like inhibitor of caspase-activated deoxyribonuclease (ICAD) and poly(ADP-ribose) polymerase (PARP).
  • Comparing NO-induced apoptosis in thymocytes from wild-type and caspase-1 knockout mice.

Main Results:

  • Pan-caspase and caspase-1 inhibitors significantly blocked NO-induced thymocyte apoptosis, while caspase-3 inhibitors had minimal effect.
  • Caspase-1 activity was upregulated following NO exposure, preceding the cleavage of ICAD and PARP.
  • Thymocytes from caspase-1 knockout mice exhibited resistance to NO-induced apoptosis compared to wild-type.

Conclusions:

  • NO induces thymocyte apoptosis through a pathway dependent on caspase-1, not caspase-3.
  • Caspase-1 directly mediates DNA fragmentation by cleaving ICAD, establishing a novel mechanism for NO-induced apoptosis.

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