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International Immunology Advance Access published online on May 20, 2005
International Immunology, doi:10.1093/intimm/dxh264
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received March 1, 2005
Accepted April 1, 2005

Article

Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria

Koji Nagaoka 1 *, Kazuhiko Takahara 1 *, Kay Tanaka 1, Hideo Yoshida 1, Ralph M. Steinman 2, Shin-ichiro Saitoh 3, Sachiko Akashi-Takamura 3, Kensuke Miyake 4, Young Sun Kang 2, Chae Gyu Park 2, and Kayo Inaba 1*

1 Laboratory of Immunobiology, Department of Animal Development and Physiology, Division of Systemic Life Science, Graduate School of Biostudies, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan
2 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
3 Division of Infectious Genetics, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
4 Division of Infectious Genetics, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; CREST, Japan Science and Technology Corporation, Tokyo, Japan

* To whom correspondence should be addressed.
Kayo Inaba, E-mail: kayo{at}lif.kyoto-u.ac.jp


  Abstract

SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (M{phi}) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium, as well as Candida albicans. We have now investigated the precise ligands and innate responses that involve SIGNR1. The interaction of SIGNR1 with FITC-dextran and E. coli was completely inhibited by LPS from E. coli and Salmonella minnesota. Using LPS from various types of rough mutants of Salmonella, we found that SIGNR1 primarily recognizes oligosaccharides in the non-reductive end of the LPS core region. In transfectants, expression of SIGNR1 enhanced the oligomerization of Toll-like receptor (TLR) 4 molecules as well as the degradation of I{kappa}B-{alpha} after stimulation with E. coli under low-serum conditions. The enhanced TLR4 oligomerization was inhibited by pre-treatment of the cells with anti-SIGNR1 mAb or with mannan. A physical association between SIGNR1 and the TLR4-MD-2 complex was also observed by immunoprecipitation. Finally, we found that transfection of SIGNR1 into the macrophage-like RAW264.7 cells resulted in significant augmentation of cytokine production. These results suggest that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate M{phi} responses.

Keywords: gram-negative bacteria; lectin; LPSs; macrophages.

*These authors contributed equally to this work.


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