Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.
Title | Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. |
Publication Type | Journal Article |
Year of Publication | 2004 |
Authors | Saleh, 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 |
Journal | Nature |
Volume | 429 |
Issue | 6987 |
Pagination | 75-9 |
Date Published | 2004 May 06 |
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 |
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. |
DOI | 10.1038/nature02451 |
Alternate Journal | Nature |
PubMed ID | 15129283 |