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Science 4 February 2005:
Vol. 307. no. 5710, pp. 734 - 738
DOI: 10.1126/science.1103685
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Reports

Nod2 Mutation in Crohn's Disease Potentiates NF-{kappa}B Activity and IL-1ß Processing

Shin Maeda,1 Li-Chung Hsu,1* Hongjun Liu,1* Laurie A. Bankston,1,3 Mitsutoshi Iimura,2 Martin F. Kagnoff,2 Lars Eckmann,2 Michael Karin1{dagger}

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 {kappa}B (NF-{kappa}B) and antibacterial defenses, but CD clinical specimens display elevated NF-{kappa}B activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-{kappa}B activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1ß (IL-1ß). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-{kappa}B activation and IL-1ß secretion.

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 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 Program on Cell Adhesion, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: karinoffice{at}ucsd.edu

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