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J. Biol. Chem., Vol. 282, Issue 20, 14975-14983, May 18, 2007

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A Critical Role of Toll-like Receptor 2 in Nerve Injury-induced Spinal Cord Glial Cell Activation and Pain Hypersensitivity^*

Donghoon Kim¹, Myung Ah Kim, Ik-Hyun Cho, Mi Sun Kim, Soojin Lee^¶, Eun-Kyeong Jo^¶, Se-Young Choi, Kyungpyo Park, Joong Soo Kim, Shizuo Akira^||, Heung Sik Na, Seog Bae Oh², and Sung Joong Lee³

From the Program in Molecular and Cellular Neuroscience, Dental Research Institute, BK21, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Korea, the Department of Physiology, Medical Science Research Center, Korea University College of Medicine, Seoul 136-705, Korea, the ^¶Department of Microbiology, Chungnam National University, Daejeon 301-747, Korea, and the ^||Department of Host Defense, Osaka University, Osaka 565-0871, Japan

The activation of spinal cord glial cells has been implicated in the development of neuropathic pain upon peripheral nerve injury. The molecular mechanisms underlying glial cell activation, however, have not been clearly elucidated. In this study, we found that damaged sensory neurons induce the expression of tumor necrosis factor-, interleukin-1, interleukin-6, and inducible nitric-oxide synthase genes in spinal cord glial cells, which is implicated in the development of neuropathic pain. Studies using primary glial cells isolated from toll-like receptor 2 knock-out mice indicate that damaged sensory neurons activate glial cells via toll-like receptor 2. In addition, behavioral studies using toll-like receptor 2 knock-out mice demonstrate that the expression of toll-like receptor 2 is required for the induction of mechanical allodynia and thermal hyperalgesia due to spinal nerve axotomy. The nerve injury-induced spinal cord microglia and astrocyte activation is reduced in the toll-like receptor 2 knock-out mice. Similarly, the nerve injury-induced pro-inflammatory gene expression in the spinal cord is also reduced in the toll-like receptor 2 knock-out mice. These data demonstrate that toll-like receptor 2 contributes to the nerve injury-induced spinal cord glial cell activation and subsequent pain hypersensitivity.

Received for publication, August 1, 2006 , and in revised form, February 22, 2007.

^* This work was supported in part by the Brain Research Center of the 21st Century Frontier Research Program (Grant M103KV010009-05K2201-00930), by the Neurobiology Research Program at the Korea Ministry of Science and Technology (Grant M10412000014-06N1200-01410), and by the Korea Research Foundation (Grant KRF-2005-070-C00096), Republic of Korea. 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 on-line version of this article (available at http://www.jbc.org) contains supplemental "Methods" and Figs. S1 and S2.

¹ Supported by the Seoul Science Fellowship.

² To whom correspondence may be addressed. Tel.: 82-2-740-8656; Fax: 82-2-762-5107; E-mail: odolbae{at}snu.ac.kr. ³ To whom correspondence may be addressed. Tel.: 82-2-740-8649; Fax: 82-2-762-5107; E-mail: sjlee87{at}snu.ac.kr.

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