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Infection and Immunity, April 2006, p. 2121-2127, Vol. 74, No. 4
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.4.2121-2127.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

NF-{kappa}B-Inducing Kinase Regulates Selected Gene Expression in the Nod2 Signaling Pathway

Qilin Pan,1 Vladimir Kravchenko,1 Alex Katz,1 Shuang Huang,1 Masayuki Ii,1 John C. Mathison,1 Koichi Kobayashi,2 Richard A. Flavell,2 Robert D. Schreiber,3 David Goeddel,4 and Richard J. Ulevitch1*

Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037,1 Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520,2 Department of Pathology and Immunology, Washington University Medical School, St. Louis, Missouri 63110,3 Tularik Inc., 1120 Veterans Boulevard, South San Francisco, California 940804

Received 21 November 2005/ Returned for modification 21 December 2005/ Accepted 5 January 2006

The innate immune system surveys the extra- and intracellular environment for the presence of microbes. Among the intracellular sensors is a protein known as Nod2, a cytosolic protein containing a leucine-rich repeat domain. Nod2 is believed to play a role in determining host responses to invasive bacteria. A key element in upregulating host defense involves activation of the NF-{kappa}B pathway. It has been suggested through indirect studies that NF-{kappa}B-inducing kinase, or NIK, may be involved in Nod2 signaling. Here we have used macrophages derived from primary explants of bone marrow from wild-type mice and mice that either bear a mutation in NIK, rendering it inactive, or are derived from NIK–/– mice, in which the NIK gene has been deleted. We show that NIK binds to Nod2 and mediates induction of specific changes induced by the specific Nod2 activator, muramyl dipeptide, and that the role of NIK occurs in settings where both the Nod2 and TLR4 pathways are activated by their respective agonists. Specifically, we have linked NIK to the induction of the B-cell chemoattractant known as BLC and suggest that this chemokine may play a role in processes initiated by Nod2 activation that lead to improved host defense.

* Corresponding author. Mailing address: Department of Immunology, IMM-12, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8219. Fax: (858) 784-8333. E-mail: ulevitch{at}scripps.edu.

Editor: A. D. O'Brien

Infection and Immunity, April 2006, p. 2121-2127, Vol. 74, No. 4
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.4.2121-2127.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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