Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Maya Saleh, John P. Vaillancourt, Rona K. Graham, Matthew Huyck, Srinivasa M. Srinivasula, Emad S. Alnemri, Martin H. Steinberg, Vikki Holan, Clinton T. Baldwin, Richard S. Hotchkiss, Timothy G. Buchman, Barbara A. Zehnbauer, Michael R. Hayden, Lindsay A. Farrer, Sophie Roy, Donald W. Nicholson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

377 Scopus citations

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-β 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.

Original languageEnglish
Pages (from-to)75-79
Number of pages5
JournalNature
Volume429
Issue number6987
DOIs
StatePublished - 6 May 2004
Externally publishedYes

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