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

Chang, KC; Unsinger, J; Davis, CG; Schwulst, SJ; Muenzer, JT; Strasser, A; Hotchkiss, RS

Author(s): Chang, KC; Unsinger, J; Davis, CG; Schwulst, SJ; Muenzer, JT; Strasser, A; Hotchkiss, RS;
Details: Publication Year 2007-03,Volume 21,Issue #3,Page 708-719
Journal Title: FASEB JOURNAL
Publication Type: Journal Article
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.
Publisher: FEDERATION AMER SOC EXP BIOL
Keywords: BH3-ONLY PROTEINS PUMA; FAMILY MEMBER BIM; IN-VIVO; IMPROVES SURVIVAL; IMMUNE-SYSTEM; AUTOREACTIVE THYMOCYTES; LYMPHOCYTE APOPTOSIS; SEPTIC MICE; FAS LIGAND; BCL-2
Publisher's Version: https://doi.org/10.1096/fj.06-6805com
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Creation Date: 2007-03-01 12:00:00