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

TitleDifferential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.
Publication TypeJournal Article
Year of Publication2004
AuthorsSaleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, Steinberg MH, Nolan V, Baldwin CT, Hotchkiss RS, Buchman TG, Zehnbauer BA, Hayden MR, Farrer LA, Roy S, Nicholson DW
JournalNature
Volume429
Issue6987
Pagination75-9
Date Published2004 May 06
ISSN1476-4687
KeywordsAfrica, 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
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.

DOI10.1038/nature02451
Alternate JournalNature
PubMed ID15129283