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Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.

Authors
  • Saleh, Maya
  • Vaillancourt, John P
  • Graham, Rona K
  • Huyck, Matthew
  • Srinivasula, Srinivasa M
  • Alnemri, Emad S
  • Steinberg, Martin H
  • Nolan, Vikki
  • Baldwin, Clinton T
  • Hotchkiss, Richard S
  • Buchman, Timothy G
  • Zehnbauer, Barbara A
  • Hayden, Michael R
  • Farrer, Lindsay A
  • Roy, Sophie
  • Nicholson, Donald W
Type
Published Article
Journal
Nature
Publisher
Springer Nature
Publication Date
May 06, 2004
Volume
429
Issue
6987
Pages
75–79
Identifiers
PMID: 15129283
Source
Medline
License
Unknown

Abstract

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.

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