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J. Biol. Chem., Vol. 282, Issue 25, 17997-18008, June 22, 2007

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Functional Analysis of Activating Receptor LMIR4 as a Counterpart of Inhibitory Receptor LMIR3^*

Kumi Izawa, Jiro Kitaura, Yoshinori Yamanishi, Takayuki Matsuoka, Toshihiko Oki, Fumi Shibata, Hidetoshi Kumagai, Hideaki Nakajima, Mari Maeda-Yamamoto, Jeffrey P. Hauchins^¶, Victor L. J. Tybulewicz^||, Toshiyuki Takai^**, and Toshio Kitamura¹

From the Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, the National Institute of Vegetable and Tea Science, National Agriculture Research Organization, 2769 Kanaya, Shizuoka 428-8501, Japan, ^¶R&D Systems, Inc., Minneapolis, Minnesota 55413, the ^||Division of Immune Cell Biology, National Institute for Medical Research, London NW7 1AA, United Kingdom, and the ^**Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Sendai 980-8575, Japan

The leukocyte mono-Ig-like receptor (LMIR) belongs to a new family of paired immunoreceptors. In this study, we analyzed activating receptor LMIR4/CLM-5 as a counterpart of inhibitory receptor LMIR3/CLM-1. LMIR4 is expressed in myeloid cells, including granulocytes, macrophages, and mast cells, whereas LMIR3 is more broadly expressed. The association of LMIR4 with Fc receptor- among immunoreceptor tyrosine-based activation motif-bearing molecules was indispensable for LMIR4-mediated functions of bone marrow-derived mast cells, but dispensable for its surface expression. Cross-linking of LMIR4 led to Lyn- and Syk-dependent activation of bone marrow-derived mast cells, resulting in cytokine production and degranulation, whereas that of LMIR3 did not. The triggering of LMIR4 and TLR4 synergistically caused robust cytokine production in accordance with enhanced activation of ERK, whereas the co-ligation of LMIR4 and LMIR3 dramatically abrogated cytokine production. Notably, intraperitoneal administration of lipopolysaccharide strikingly up-regulated LMIR3 and down-regulated LMIR4, whereas that of granulocyte colony-stimulating factor up-regulated both LMIR3 and LMIR4 in granulocytes. Cross-linking of LMIR4 in bone marrow granulocytes also resulted in their activation, which was enhanced by lipopolysaccharide. Collectively, these results suggest that the innate immune system is at least in part regulated by the qualitative and quantitative balance of the paired receptors LMIR3 and LMIR4.

Received for publication, February 26, 2007 , and in revised form, April 13, 2007.

^* This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology and the Ministry of Health and Welfare, Japan. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AB292061 [GenBank] and AB292062 [GenBank] .

¹ To whom correspondence should be addressed. Tel.: 81-3-5449-5759; Fax: 81-3-5449-5428; E-mail: kitamura{at}ims.u-tokyo.ac.jp.

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