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Nod2 Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing

Science, 4 February 2005
Vol. 307, Issue 5710, p. 734-738
DOI: 10.1126/science.1103685

Nod2 Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing

  1. Shin Maeda1,
  2. Li-Chung Hsu1,*,
  3. Hongjun Liu1,*,
  4. Laurie A. Bankston1,3,
  5. Mitsutoshi Iimura2,
  6. Martin F. Kagnoff2,
  7. Lars Eckmann2,
  8. Michael Karin1,
  1. 1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0723, USA.
  2. 2 Laboratory of Mucosal Immunology, Departments of Medicine and Pediatrics, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0723, USA.
  3. 3 Program on Cell Adhesion, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  1. To whom correspondence should be addressed. E-mail: karinoffice{at}ucsd.edu
  • * These authors contributed equally to this work.

Abstract

Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor κB (NF-κB) and antibacterial defenses, but CD clinical specimens display elevated NF-κB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-κB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1β (IL-1β). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-κB activation and IL-1β secretion.

    • Received for publication 5 August 2004.
    • Accepted for publication 8 December 2004.

    Citation:

    S. Maeda, L.-C. Hsu, H. Liu, L. A. Bankston, M. Iimura, M. F. Kagnoff, L. Eckmann, and M. Karin, Nod2 Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing. Science 307, 734-738 (2005).

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