Abstract
Caspase-11 is an essential mediator of septic shock response and caspase-11-deficient mice are resistant to LPS-induced shock. Here we report that LPS-induced caspase-11 regulates lymphocyte apoptosis by activating both caspase-3 and caspase-7. The activation of caspase-11 preceded that of caspase-1 and caspases-3/-7, and in the absence of caspase-11, the activation of caspases-3/-7 was significantly reduced. The early activation of caspases-3/-7 by caspase-11 was not affected by blocking of caspase-1 activity and IL-1β release, implying that caspase-11 activates caspases-3/-7 independently of caspase-1 activation. Furthermore, we show that caspase-11-mediated apoptosis under septic condition is Bid-independent. Our work suggests that the human homologue of caspase-11 may be an effective therapeutic target for treatment of septic shock.
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Abbreviations
- CARD:
-
caspase recruitment domain
- IL:
-
interleukin
- LPS:
-
lipopolysaccharides
- TUNEL:
-
TdT-mediated dUTP digoxigenin nick-end labeling
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Acknowledgements
We thank Mike Boyce and Dr. Roberto Sanchez-Olea for critical reading of the manuscript, Dr. Stanley Korsmeyer for providing Bid-deficient mice, Dr. Anu Srinivasan for providing CM1 antibody, Dr. Toshiyuki Nakagawa for helpful advice, Hong Zhu for generating monoclonal antibodies and Christian Mahlke for technical assistance in mouse genotyping. This work was supported by a grant from the National Institute of Aging (AG12859) to J Yuan.
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Kang, S., Wang, S., Kuida, K. et al. Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response. Cell Death Differ 9, 1115–1125 (2002). https://doi.org/10.1038/sj.cdd.4401087
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DOI: https://doi.org/10.1038/sj.cdd.4401087
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