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J. Biol. Chem., Vol. 281, Issue 39, 29054-29063, September 29, 2006

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Differential Release and Distribution of Nod1 and Nod2 Immunostimulatory Molecules among Bacterial Species and Environments^*

Mizuho Hasegawa, Kangkang Yang, Masahito Hashimoto, Jong-Hwan Park^¶, Yun-Gi Kim, Yukari Fujimoto^||, Gabriel Nuñez^¶, Koichi Fukase^||, and Naohiro Inohara¹

From the Department of Pathology and ^¶Comprehensive Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan 48109, the Department of Nanostructure and Advanced Materials, Kagoshima University, Korimoto 1-21-40, Kagoshima 890-0065, Japan and the ^||Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama 1-1, Toyonaka, Osaka 560-0043, Japan

Nod1 and Nod2 are intracellular proteins that are involved in recognition of bacterial molecules and their genetic variations have been linked to several inflammatory diseases that are strongly affected by environmental factors. However, the distribution of Nod1- and Nod2-stimulatory molecules in different bacterial species and environments is unknown. Here we established a quantitative bioassay to screen and characterize Nod1- and Nod2-stimulatory activities in different environmental sites and bacterial species. Using this system, we found that common environments including foods and soils contain high levels of Nod1- and Nod2-stimulatory activities. Several Bacillus species were identified to possess the highest Nod1-stimulatory activity among soil bacteria. Unlike other immunostimulatory molecules, the higher level of Nod1-stimulatory activity was found in the culture supernatant and not in extracts from whole cell bacteria. Nod1-stimulatory molecules were highly stable at extreme pH and boiling conditions and were synthesized in an amidase- and sltY-independent manner. These results suggest a novel mechanism by which bacteria present in the environment stimulate the host immune system through Nod1.

Received for publication, March 21, 2006 , and in revised form, July 26, 2006.

^* This work was supported by grants from the National Institutes of Health (to N. I. and G. N.) and the Ministry of Education, Science, Sports and Culture, Japan (to K. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1150 W. Medical Center Dr., Ann Arbor, MI 48109. Tel.: 734-936-3317; Fax: 734-647-9654; E-mail: ino{at}umich.edu.

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