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

Bibliographic Collection: 
MOCA Reference, APE
Publication Type: Journal Article
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
Year of Publication: 2004
Journal: Nature
Volume: 429
Issue: 6987
Pagination: 75-9
Date Published: 2004 May 6
Publication Language: eng
ISSN: 1476-4687
Keywords: Africa, African Americans, Alzheimer Disease, Animals, Apoptosis, Base Sequence, Case-Control Studies, Caspase 12, Caspases, Concanavalin A, Cytokines, Endoplasmic Reticulum, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Inflammation, Lipopolysaccharides, NF-kappa B, Polymorphism, Single Nucleotide, Primates, Sepsis

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.

DOI: 10.1038/nature02451
Alternate Journal: Nature