Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms (original) (raw)

Nature volume 429, pages 75–79 (2004)Cite this article

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.

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Acknowledgements

We thank S. Menard, B. Simpson and the Granby Zoo for non-invasive samples for primate sequencing, and the West Island and Côte Des Neiges Black Community Associations for coordinating blood donor clinics. M.S. is supported by a CIHR postdoctoral fellowship; T.G.B. is supported by a grant from the NIGMS; L.A.F. is supported in part by grants from the NIH.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Pharmacology, Merck Frosst Centre for Therapeutic Research, Montreal, H9H 3L1, Quebec, Canada
    Maya Saleh, John P. Vaillancourt, Sophie Roy & Donald W. Nicholson
  2. Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, British Columbia, V5Z 4H4, Vancouver, Canada
    Rona K. Graham & Michael R. Hayden
  3. Departments of Medicine (Genetics Program & Hematology/Oncology Section), Neurology and Genetics & Genomics, and Center for Human Genetics, Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health, Massachusetts, 02118, Boston, USA
    Matthew Huyck, Martin H. Steinberg, Vikki Nolan, Clinton T. Baldwin & Lindsay A. Farrer
  4. Hematology/Oncology Section), Neurology and Genetics & Genomics, and Center for Human Genetics, Boston University School of Medicine and Departments of Epidemiology and Biostatistics, Boston University School of Public Health,
    Matthew Huyck, Martin H. Steinberg, Vikki Nolan, Clinton T. Baldwin & Lindsay A. Farrer
  5. Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA
    Srinivasa M. Srinivasula & Emad S. Alnemri
  6. Department of Anesthesiology, Department of Surgery, Washington University School of Medicine, St Louis, 63110, Missouri, USA
    Richard S. Hotchkiss & Timothy G. Buchman
  7. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, 63110, Missouri, USA
    Barbara A. Zehnbauer

Authors

  1. Maya Saleh
  2. John P. Vaillancourt
  3. Rona K. Graham
  4. Matthew Huyck
  5. Srinivasa M. Srinivasula
  6. Emad S. Alnemri
  7. Martin H. Steinberg
  8. Vikki Nolan
  9. Clinton T. Baldwin
  10. Richard S. Hotchkiss
  11. Timothy G. Buchman
  12. Barbara A. Zehnbauer
  13. Michael R. Hayden
  14. Lindsay A. Farrer
  15. Sophie Roy
  16. Donald W. Nicholson

Corresponding author

Correspondence toDonald W. Nicholson.

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Competing interests

I am Vice President of Merck Research Laboratories and several of the authors are also employees of Merck. Although it is unlikely that these individuals or the company would gain or lose financially through publication of this paper, it is a possibility. It is, however, highly unlikely.

Supplementary information

Supplementary Information

Supplementary methods and tables showing: 1) Subgroup breakdown of genotype and allele frequency of T125 and T125C in different ethnic backgrounds; 2) Codon 125 in humans and counterparts in non-human primates, rodents and representative human cell-lines. (DOC 81 kb)

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Saleh, M., Vaillancourt, J., Graham, R. et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms.Nature 429, 75–79 (2004). https://doi.org/10.1038/nature02451

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