Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Maya Saleh, John P. Vaillancourt, Rona K. Graham, Matthew Huyck, Srinivasa M. Srinivasula, Emad S. Alnemri, Martin H. Steinberg, Vikki Nolan, Clinton T. Baldwin, Richard S. Hotchkiss, Timothy G. Buchman, Barbara A. Zehnbauer, Michael R. Hayden, Lindsay A. Farrer, Sophie Roy and Donald W. Nicholson ()
Additional contact information
Maya Saleh: Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research
John P. Vaillancourt: Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research
Rona K. Graham: University of British Columbia
Matthew Huyck: Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health
Srinivasa M. Srinivasula: Kimmel Cancer Institute, Thomas Jefferson University
Emad S. Alnemri: Kimmel Cancer Institute, Thomas Jefferson University
Martin H. Steinberg: Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health
Vikki Nolan: Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health
Clinton T. Baldwin: Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health
Richard S. Hotchkiss: Washington University School of Medicine
Timothy G. Buchman: Washington University School of Medicine
Barbara A. Zehnbauer: Washington University School of Medicine
Michael R. Hayden: University of British Columbia
Lindsay A. Farrer: Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health
Sophie Roy: Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research
Donald W. Nicholson: Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research

Nature, 2004, vol. 429, issue 6987, 75-79

Abstract: 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)1,2. 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 disease3. 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.

Date: 2004
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DOI: 10.1038/nature02451

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