Multiple triggers of cell death in sepsis: Death receptor and mitochondrial-mediated apoptosis

Katherine C. Chang, Jacqueline Unsinger, Christopher G. Davis, Steven J. Schwulst, Jared T. Muenzer, Andreas Strasser, Richard S. Hotchkiss*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

Lymphocyte apoptosis plays a central role in the pathophysiology of sepsis. Lymphocyte apoptosis was examined in mice with defective death receptor pathways due to transgenic expression of a dominant negative mutant of Fas-associated death domain (FADD-DN) or Bid-/- and in mice with defective mitochondrial-mediated pathways due to loss of Bim-/-, Puma-/-, or Noxa-/-. FADD-DN transgenic and Bid -/- mice had significant albeit incomplete protection, and this protection was associated with increased survival. Surprisingly, splenic B cells were also protected in FADD-DN mice although transgene expression was confined to T cells, providing evidence for an indirect protective mechanism. Bim -/- provided virtually complete protection against lymphocyte apoptosis whereas Puma-/- and Noxa-/- mice had modest or no protection, respectively. Bim-/- mice had improved survival, and adoptive transfer of splenocytes from Bim-/- mice into Rag 1 -/- mice demonstrated that this was a lymphocyte intrinsic effect. The improved survival was associated with decreased interleukin (IL) -10 and IL-6 cytokines. Collectively, these data indicate that numerous death stimuli are generated during sepsis, and it therefore appears unlikely that blocking a single "trigger" can inhibit apoptosis. If siRNA becomes practical therapeutically, proapoptotic proteins would be potential targets.

Original languageEnglish (US)
Pages (from-to)708-719
Number of pages12
JournalFASEB Journal
Volume21
Issue number3
DOIs
StatePublished - Mar 2007

Keywords

  • Cytokines
  • Endotoxin
  • Necrosis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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