TY - JOUR
T1 - Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms
AU - Saleh, Maya
AU - Vaillancourt, John P.
AU - Graham, Rona K.
AU - Huyck, Matthew
AU - Srinivasula, Srinivasa M.
AU - Alnemri, Emad S.
AU - Steinberg, Martin H.
AU - Holan, Vikki
AU - Baldwin, Clinton T.
AU - Hotchkiss, Richard S.
AU - Buchman, Timothy G.
AU - Zehnbauer, Barbara A.
AU - Hayden, Michael R.
AU - Farrer, Lindsay A.
AU - Roy, Sophie
AU - Nicholson, Donald W.
N1 - Funding Information:
Acknowledgements We thank M. Takahashi, M. Yoshii, M. Omotezako, Y. Ariji, S. Abiko, W. Yamanobe and K. Tabei for their assistance. We also thank all the other members of the SNP Research Center, RIKEN, for their contribution to the completion of our study. This work was supported by a grant from the Japanese Millennium Project.
PY - 2004/5/6
Y1 - 2004/5/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=2342457148&partnerID=8YFLogxK
U2 - 10.1038/nature02451
DO - 10.1038/nature02451
M3 - Article
C2 - 15129283
AN - SCOPUS:2342457148
SN - 0028-0836
VL - 429
SP - 75
EP - 79
JO - Nature
JF - Nature
IS - 6987
ER -