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Published online before print April 2, 2007

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(Journal of Leukocyte Biology. 2007;82:177-183.)
© 2007 by Society for Leukocyte Biology

MDP-induced interleukin-1ß processing requires Nod2 and CIAS1/NALP3

Qilin Pan^*, John Mathison^*, Colleen Fearns^*, Vladimir V. Kravchenko^*, Jean Da Silva Correia^*, Hal M. Hoffman, Koichi S. Kobayashi, John Bertin^,1, Ethan P. Grant^,1, Anthony J. Coyle^,2, Fayyaz S. Sutterwala^||, Yasunori Ogura^||, Richard A. Flavell^|| and Richard J. Ulevitch^*,3

^* Department of Immunology, The Scripps Research Institute, La Jolla, California, USA;
Ludwig Institute of Cancer Research and University of California at San Diego, La Jolla, California, USA;
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts, USA;
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; and
^|| Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

³ Correspondence: Department of Immunology, IMM12, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: ulevitch{at}scripps.edu

Nucleotide-binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (MDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. Cold-induced autoinflammatory syndrome 1 (CIAS1)/NACHT domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) has been suggested to be sufficient for MDP-dependent release of mature IL-1ß, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that MDP-induced IL-1ß release requires Nod2 and CIAS1/NALP3 as well as receptor-interacting protein-2 (Rip2), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. In contrast, MDP-dependent IL-6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL-1ß production and allow for further studies of the role of these proteins within the broader context of inflammatory disease.

Key Words: cytokine • inflammation • PAMP • NLR

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