학술논문
Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.
Document Type
Article
Author
Saleh, Maya; Vaillancourt, John P.; Graham, Rona K.; Huyck, Matthew; Srinivasula, Srinivasa M.; Alnemri, Emand 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.
Source
Subject
*APOPTOSIS
*CYTOKINES
*SEPSIS
*ENDOTOXINS
*CYTOCHEMISTRY
*IMMUNOLOGY
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Language
ISSN
0028-0836
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. [ABSTRACT FROM AUTHOR]