title: Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.
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.
authors.affiliation: Department of Biochemistry, Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research, Montreal, Quebec H9H 3L1, Canada.
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
authors.forename: John P
authors.initials: JP
authors.lastname: Vaillancourt
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Matthew
authors.initials: M
authors.lastname: Huyck
authors.forename: Srinivasa M
authors.initials: SM
authors.lastname: Srinivasula
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
authors.forename: Vikki
authors.initials: V
authors.lastname: Nolan
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Buchman
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Zehnbauer
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Donald W
authors.initials: DW
authors.lastname: Nicholson
mesh_terms: D000349:Africa / Q000208:ethnology; D001741:Black or African American / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D016022:Case-Control Studies; D053454:Caspase 12; D020169:Caspases / Q000737:chemistry / Q000235:genetics*; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011323:Primates / Q000235:genetics; D018805:Sepsis / Q000235:genetics*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D003208:Concanavalin A; C506444:CASP12 protein, human; D053454:Caspase 12; D020169:Caspases