추천논문
이성중 (Sung Joong Lee)
서울대학교 치과대학
[2009년 1월]
Brain, 2008 131(11):3019-3033; doi:10.1093/brain/awn230
Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death
Ik-Hyun Cho1,*, Jinpyo Hong1,*, Eun Cheng Suh2, Jae Hwan Kim3, Hyunkyoung Lee1, Jong Eun Lee3, Soojin Lee4, Chong-Hyun Kim5, Dong Woon Kim6, Eun-Kyeong Jo7,8, Kyung Eun Lee2, Michael Karin9 and Sung Joong Lee1
1Program in Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, 2Department of Pharmacology, School of Medicine, Ewha Womans University, 3Department of Anatomy and Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, Seoul, 4Department of Microbiology, School of Bioscience and Biotechnology, Chungnam National University, Daejeon, 5Center for Neural Science, University of Science and Technology, Korea Institute of Science and Technology, Seoul, 6Department of Anatomy, 7Department of Microbiology, 8Infection Signaling Network Research Center, Chungnam National University College of Medicine, Daejeon, Korea and 9Department of Pharmacology, School of Medicine, University of California at San Diego, San Diego, CA, USA
Correspondence to: Sung Joong Lee, PhD, Program in Molecular and Cellular Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, Korea and Michael Karin, PhD, Department of Pharmacology, School of Medicine, University of California at San Diego, San Diego, CA, USA.
Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikk{beta} conditional knockout mice (LysM-Cre/Ikk{beta}F/F) in which the Ikk{beta} gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced I{kappa}B kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (Ikk{beta}F/F), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30% in LysM-Cre/Ikk{beta}F/F mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)-{alpha} and interleukin (IL)-1{beta}. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/IkkβF/F mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-{alpha} and IL-1{beta} expression. Based on these data, we concluded that IKK/nuclear factor-{kappa}B dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.
Key Words: excitotoxicity; hippocampus; IKK{beta}; kainic acid; microglia
Abbreviations: CA1, cornu ammonis 1; CA3, cornu ammonis 3; CD11b, cluster of differentiation molecule 11b; GFAP, glial fibrillary acidic protein; HMGB-1, high-mobility group box-1; Iba-1, ionized calcium binding adaptor molecule-1; IL-1{beta}, interleukin-1{beta}; IKK, I{kappa}B kinase; IR, immunoreactive; KA, kainic acid; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; NF-{kappa}B, nuclear factor-kappa B; NG2, neuron-glial antigen 2; OHSCs, organotypic hippocampal slice cultures; PI, propidium iodide; PM{pai}, peritoneal macrophages; TLR, toll-like receptor; TNF-{alpha}, tumour necrosis factor-{alpha}; tPA, tissue plasminogen activator
추천자 : 최세영 (서울대학교 치과대학, 조교수)
추천이유 : 많은 신경학적 질환에 있어서 미세아교세포(microglial cell)가 활성화되는 것으로 알려져 있는데, 활성화된 미세아교세포는 neurotoxic mediator를 분비하여 신경세포사멸을 유도한다는 가설과 neurotrophic mediator을 분비하여 신경손상을 최소화하여 손상을 치유하는데 관여한다는 가설이 주장되어 오고 있습니다. 그러나, 아직까지 미세아교세포의 활성화의 정확한 기능은 밝혀지지 않았습니다.
본 연구에서는 CNS의 미세아교세포를 포함한 myeloid lineage 세포에서만 특이적으로 IKK{beta} gene이 결핍된 IKK{beta} 조건부형질전환 (LysM-Cre/Ikk{beta} (F/F)) 쥐에 많은 신경 질환의 주요 기전중의 하나인 흥분독성신경세포사멸 (kainite-induced hippocampal cell death model) 모델을 적용하여 IKK/nuclear factor-kappa B 의존성 미세아교세포의 활성화는 염증매개체의 유도를 통하여 흥분독성에 의한 해마신경세포사멸에 있어서 독성효과를 나타낸다는 것을 밝힌 것으로 신경학분야에서 획기적인 연구 결과라고 생각되어 추천합니다.
About the Author
EDUCATION & CAREER
1987 - 1992 Seoul National University B.S. Microbiology
1994 - 1999 Ph.D. Department of Cell Biology (Neuroimmunology major)
The University of Alabama at Birmingham
2/2000 - 9/2000 Post-doctoral fellow
Department of Cell Biology, University of Alabama at Birmingham
10/2000 - 1/2003 Post-doctoral fellow
Department of Pharmacology, The University of California at San Diego
2/1/2003 - 3/2005 Full-time instructor
Department of Oral Physiology
College of Dentistry, Seoul National University
4/2005 - present Assistant Professor
Department of Oral Physiology
College of Dentistry, Seoul National University
RESEARCH EXPERIENCE
1994 - 1999 Graduate Student, The University of Alabama at Birmingham, Mentor: Dr. Etty N. Benveniste
Transcriptional regulation and the function of ICAM-1 and Fas (CD95) expression in glial cells
1999 - 9/2000 Post-doctoral Fellow, The University of Alabama at Birmingham, Mentor: Dr. Etty N. Benveniste
Cloning of ICAM-1 interacting protein using yeast two-hybrid system
10/2000 - 1/2003 Post-doctoral Fellow, The University of California at San Diego, Mentor: Dr. Michael Karin
Generation of glial cell-specific IKK and JNK1 conditional knock out mice; The role of glial cell-specific NF- B or JNK activation in demyelinating and neurodegenerative diseases.
2/1/2003 - present College of Dentistry, Seoul National University
Role of Schwann cells in peripheral nerve regeneration; Role of TLR on glial cells in the neurodegeneration; Role of glial cell activation in the CNS inflammatory diseases in vivo.
Professional Honors
1999 Ad Hoc Reviewer for Journal Brain Research Bulletin
2000 Ad Hoc Reviewer for Journal Brain Research
2005 Ad Hoc Reviewer for Immunology
2006 Ad Hoc Reviewer for Neurobiology of Disease
2007 Ad Hoc member of Ireland Health Research Board
2008 Ad Hoc Reviewr for Cytokine
2008 Ad Hoc Reviewr for Neuroscience
Awards
2001-1/2003 National Multiple Sclerosis Society Post-doctoral Fellowship
PUBLICATIONS
1. Kwon, J., Lee, S. J., and E. N. Benveniste. 1996. A 3' cis-acting element is involved in TNF- gene expression in astrocytes. J. Biol. Chem. 271: 22383-22390.
2. Shrikant, P., Lee, S. J., Kalvakolanu, I., Ransohoff, R. M., and E. N. Benveniste. 1996. Stimulus-specific inhibition of intercellular adhesion molecule-1 gene expression by TGF- . J. Immunol. 157: 892-900.
3. Agrawal, A., Lee, S. J., Carson, M., Narayana, S. V. L., Greenhough, T. J., and J. E. Volanakis. 1997. Site-directed mutagenesis of the phosphocholine-binding site of human C-reactive protein. J. Immunol. 158: 345-350.
4. Goldsmith, J. F., Lee, S. J., Jiang, J., and S. J. Frank. 1997. Growth hormone induces detergent insolubility of GH receptors in IM-9 cells. Am. J. Physiol. 273: E932-E941.
5. Lee, S. J., Hou, J., and E. N. Benveniste. 1998. Transcriptional regulation of intercellular adhesion molecule-1 in astrocytes involves NF- B and C/EBP isoforms. J. Neuroimmunol. 92: 196-207.
6. Lee, S. J., Park, J. Y., Hou, J., and E. N. Benveniste. 1999. Transcriptional regulation of the intercellular adhesion molecule-1 gene by proinflammatory cytokines in human astrocytes. GLIA. 25: 21-32.
7. Lee, S. J., and E. N. Benveniste. 1999. Adhesion molecule expression and regulation on cells of the central nervous system. J. Neuroimmunol. 98:77-88.
8. Lee, S. J., Zhou, T., Choi C., Wang, Z., and E. N. Benveniste. 2000. Differential regulation and function of Fas expression on glial cells. J. Immunol. 164:1277-1285.
9. Lee, S. J., Drabik, K., Van Wagoner, N. J., Lee, S., Choi, C., Dong, Y., and E. N. Benveniste. 2000. ICAM-1-induced expression of proinflammatory cytokines and chemokines in astrocytes: Involvement of ERK and p38 MAP kinases. J. Immunol. 165: 4658-4666.
10. Choi, C., Xu, X., Oh, J. W., Lee, S. J., Gillespie, G. Y., Park, H., Jo, H., and E. N. Benveniste. 2001. Fas- induced expression of chemokines in human glioma cells: Involvement of ERK1/ERK2 and p38 MAP kinases. Cancer Res. 61 (7): 3084-3091.
11. Lee, S. J., Drabik, K., E. N. Benveniste. 2001. Cloning of rat calcium-modulating cyclophilin ligand. DNA Seq. 12 (3): 209-213.
12. Lee, S. J. and S. Lee. 2002. Toll-like receptors and inflammation in the CNS. Current Drug Targets-Inflammation & Allergy. 1: 181-191. (IF: 4.274)
13. Sim, M-Y., Yeon, K-Y., Choi, S-Y., Lee, S.J., Park, K., Lee, J., Oh, S.B., Kim. J-S. 2003. Modulation of calcium currents by nociceptin/orphanin FQ in trigeminal neurons. Int. J. Oral Biol., 28(2): 43-47. (Aug. 1.)
14. Kim, J.G., Lee S. J., and Kagnoff M.F. 2004. Nod1 is an essential signal transducer in intestinal epithelial cells infected with bacteria that avoid recognition by toll-like receptors. Infection & Immunity, 72(3): 1487-1495. (Mar. 1) (IF: 4.033)
15. Lee, S., Hong, J., Choi, S., Oh, S. B., Park, K., Kim, J. S., Karin, M., >S. J. Lee. 2004. CpG oligonucleotides induce expression of proinflammatory cytokines and chemokines in astrocytes: the role of c-Jun N-terminal kinase in CpG ODN-mediated NF- B activation. J. Neuroimmunol. 153:50-63. (Aug. 1) (IF: 2.704)
16. Lee, M.H., Yeon, K-Y., Fang, Z., Kim, M.S., Park, C-K., Choi, S-Y., Lee, S. J., Park, K., Lee, J-H., Oh, S.B., J.S. Kim. 2004. Differential effects of transient receptor potential vanilloid ligands on calcium currents. Int. J. Oral Biol., 29(3):93-98. (Sept. 30.)
17. Lee, H., Park, C., Choi, S., Oh, S. B., Park, K., Kim, J., S. J. Lee. 2004. Double-stranded RNA induces inflammatory gene expression in Schwann cells: Implication in the Wallerian degeneration. Korean J. Physiol. Pharmacol. 8:253-257. (Oct. 1)
18. Kyu-Young Yeon, Mi-Young Sim, Se-Young Choi, Sung Joong Lee, Kyungpyo Park, Joong Soo Kim, Jong-Heun Lee, Kyung-Mi Lee and Seog Bae Oh. 2004. Molecular Mechanisms Underlying Calcium Current Modulation By Nociceptin. Neuroreport. 15(14):2205-9. (Oct. 5) (IF: 2.351)
19. Li, J., Ha, Y-M., Ku, N-Y, Choi, S-Y, Lee, S. J., Oh, S.B. Kim, J-S, Lee, J-H, Lee, E.B., Song, Y.W., Park, K., 2004. Inhibitory effects of autoantibodies on the muscarinic receptors in Sjogren's syndrome. Lab. Invest. 84:1430-1438. (Nov. 1) (IF: 3.702)
20. Bang, G-Y., Pioa, Z.G., Choi, S-Y., Lee, S. J., Park, K., Kim, J.S., S.B. Oh. 2004. Changes in expression of high-voltage-activated calcium channel in facial motoneurons following facial nerve injury. Int. J. Oral Biol., 29(4):127-132. (Dec. 31.)
21. Hyo-Chel Ryu, Zheng Gen Piao, Se-Young Choi, Sung Joong Lee, Kyungpyo Park, Joong Soo Kim, and Seog Bae Oh, 2005. ABAergic Synaptic Input to Mesencephalic Trigeminal Neurons in Rat. Int. J. Oral Biol., 30(2):71-76. (Jun. 30.)
22. Lee, MH, Yeon, K-Y, Park, C-K, Li, H-Y, Fang Z, Kim, MS, Choi, S-Y, Lee, S. J., Lee, S, Park K, Lee, J-H, Kim JS, S.B. Oh. 2005. Eugenol inhibits calcium currents in dental afferent neurons. J. Dent. Res. 84(9):848-851. (Sep. 1) (IF: 3.131)
23. Park, DJ, Park, SA, Yoon, TG, Lee, S. J., Yum, KW, HJ Kim. 2005. Bupivacaine induces apoptosis via ROS in the Schwann cell line. J. Dent. Res. 84(9):852-857. (Sep. 1) (IF: 3.131)
24. Park C, S Lee, I Cho, H Lee, D Kim, S-Y Choi, S B Oh, K Park, J S Kim, and Sung Joong Lee, 2006. A TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: Differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. GLIA. 53:248-256. (Feb.1) (IF: 5.013)
25. Kim MS, Park CK, Yeon KY, Li HY, Jung SJ, Choi SY, Lee SJ, Park K, Kim JS, Oh SB. 2006. Involvement of transient receptor potential vanilloid-1 in calcium current inhibition by capsaicin. Neuroreport. 17(2):145-149. (Feb. 6) (IF: 2.351)
26. Cho IH, Chung YM, Park CK, Park SH, Li HY, Kim D, Piao ZG, Choi SY, Lee SJ, Park K, Kim JS, Oh SB. 2006 Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat. Brain Res. 1072(1): 208-214. (Feb 9) (IF: 2.386)
27. Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB. 2006. Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain. 121(3):219-31. (Apr. 1) (IF: 4.061)
28. Koo NY, Li J, Hwang SM, Choi SY, Lee SJ, Oh SB, Kim JS, Lee JH, Park K. 2006. Molecular cloning and functional expression of a sodium bicarbonate cotransporter from guinea-pig parotid glands. Biochem. Biophys. Res. Commun. 342(4):1114-22. (Apr. 21). (IF: 3.0)
29. Piao L, Ying Li H, Park CK, Cho IH, Piao ZG, Jung SJ, Choi SY, Lee SJ, Park K, Kim JS, Oh SB Mechanosensitivity of voltage-gated K(+) currents in rat trigeminal ganglion neurons. J. Neurosci. Res. 2006 May 15;83(7):1373-80. (IF: 3.737)
30. Park CK, Kim MS, Fang Z, Li HY, Jung SJ, Choi SY, Lee SJ, Park K, Kim JS, Oh SB. Functional expression of thermo-transient receptor potential channels in dental primary afferent neurons: implication for tooth pain. J Biol Chem. 2006 Jun 23;281(25):17304-11. (IF: 5.808)
31. Li J, Koo NY, Cho IH, Kwon TH, Choi SY, Lee SJ, Oh SB, Kim JS, Park K. Expression of sodium bicarbonate cotransporter and its role in pHi regulation in guinea pig salivary glands.
Am J Physiol Gastrointest Liver Physiol. 2006 Dec;291(6):G1031-40. (IF: 3.479)
32. Lee H, Choi S-Y, Oh SB, Park K, Kim JS, Lee SJ. Damaged neuronal cells induce inflammatory gene expression in Schwann cells. Int. J. Oral Biol., 31(3):87-92. (Sep. 30.)
33. Choi SY, Li J, Jo SH, Lee SJ, Oh SB, Kim JS, Lee JH, Park K. Desipramine inhibits na+/h+ exchanger in human submandibular cells. J Dent Res. 2006 Sep;85(9):839-43. (IF: 3.131)
34. Li J, Lee S, Choi SY, Lee SJ, Oh SB, Lee JH, Chung SC, Kim JS, Lee JH, Park K. Effects of pilocarpine on the secretory acinar cells in human submandibular glands. Life Sci. 2006 Nov 25;79(26):2441-7. (IF: 2.158)
35. Park CK, Li HY, Yeon KY, Jung SJ, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB. Eugenol inhibits sodium currents in dental afferent neurons. J Dent Res. 2006 Oct;85(10):900-4. (IF: 3.131)
36. Lee H, Jo EK, Choi SY, Oh SB, Park K, Soo Kim J, Lee SJ. Necrotic neuronal cells induce inflammatory Schwann cell activation via TLR2 and TLR3: Implication in Wallerian degeneration. Biochem Biophys Res Commun. 2006 Nov 24;350(3):742-7. (IF: 3.0)
37. Yang CS, Lee JS, Song CH, Hur GM, Lee SJ, Tanaka S, Akira S, Paik TH, Jo EK.Protein kinase C zeta plays an essential role for Mycobacterium tuberculosis-induced extracellular signal-regulated kinase 1/2 activation in monocytes/macrophages via Toll-like receptor 2.
Cell Microbiol. 2007, Feb. 9, 9(2) : 382-396. (IF: 6.097)
38. Lee H, Park C, Cho IH, Kim HY, Jo EK, Lee S, Kho HS, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. Double-stranded RNA Induces iNOS Gene Expression in Schwann Cells, Sensory Neuronal Death, and Peripheral Nerve Demyelination. Glia. 2007, 55:712-722. (IF: 5.013)
39. Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, Choi SY, Park K, Kim JS, Akira S, Na HS, Oh SB, Lee SJ. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem. 2007, May 18;282(20):14975-14983. (IF:5.808)
40. Yoshida H, Imaizumi T, Lee SJ, Tanji K, Sakaki H, Matsumiya T, Ishikawa A, Taima K, Yuzawa E, Mori F, Wakabayashi K, Kimura H, Satoh K. Retinoic acid-inducible gene-I mediates RANTES/CCL5 expression in U373MG human astrocytoma cells stimulated with double-stranded RNA. Neurosci. Res. 2007, 58:199-206. (IF: 1.953)
41. Ko HG, Lee SJ, Son H, Kaang BK. Null effect of antidepressants on the astrocytes-mediated proliferation of hippocampal progenitor cells in vitro. Mol. Pain 2007 Jun 15;3(1):16.
42. Li HY, Park CK, Jung SJ, Choi SY, Lee SJ, Park K, Kim JS, Oh SB. Eugenol inhibits K+ currents in trigeminal ganglion neurons. J Dent Res. 2007 Sep;86(9):898-902.
43. Yang CS, Lee HM, Lee JY, Kim JA, Lee SJ, Shin DM, Lee YH, Lee DS, El-Benna J, Jo EK. Reactive oxygen species and p47phox activation are essential for the Mycobacterium tuberculosis-induced pro-inflammatory response in murine microglia. J. Neuroinflammation. 2007 Nov 26;4:27.
44. Park C, Cho I-H, Kim D, Jo E-K, Choi S-Y, Oh SB, Park K, Kim JS, Lee SJ. Toll-like receptor 2 contributes to glial cell activation and heme oxygenase-1 expression in traumatic brain injury. Neuroscience Lett. 2008 Jan 31;431(2):123-8.
45. Yang CS, Shin DM, Lee HM, Son JW, Lee SJ, Akira S, Gougerot-Pocidalo MA, El-Benna J, Ichijo H, Jo EK. ASK1-p38 MAPK-p47phox activation is essential for inflammatory responses during tuberculosis via TLR2-ROS signalling. Cell Microbiol. 2008 Mar;10(3):741-54.
46. Koo NY, Li J, Hwang SM, Choi SY, Lee SJ, Oh SB, Kim JS, Lee EB, Song YW, Park K. Functional epitope of muscarinic type 3 receptor which interacts with autoantibodies from Sjogren's syndrome patients. Rheumatology (Oxford). 2008 Jun;47(6):828-33.
47. Shin DM, Yang CS, Yuk JM, Lee JY, Kim KH, Shin SJ, Takahara K, Lee SJ, Jo EK. Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1. Cell Microbiol. 2008 Aug; 10(8): 1608-1621.
48. Shin DM, Yang CS, Lee JY, Lee SJ, Choi HH, Lee HM, Yuk JM, Harding CV, Jo EK. Mycobacterium tuberculosis lipoprotein-induced association of TLR2 with protein kinase C xi in lipid rafts contributes to reactive oxygen species-dependent inflammatory signaling in macrophages.Cell Microbiol. 2008 Sep. 10(9):1893-1905.
49. Ik-Hyun Cho, Jinpyo Hong, Eun Cheng Suh, Hyunkyong Lee, Soojin Lee, Eun-Kyeong Jo, KyungEun Lee, Michael Karin and Sung Joong Lee, Role of microglial IKK in kainic acid-induced hippocampal neuronal cell death. Brain. 2008. Nov. 131:3019-3033. (IF:8.568)
50. Lee H, Park K, Kim JS, Lee SJ. Vasoactive intestinal peptide inhibits TLR3-induced nitric oxide production in Schwann cells and subsequent sensory neuronal death. J. Neurosci. Res. 2009. 97(1):171-178.
51. Kim D, Lee S, Lee SJ. Toll-like receptors in peripheral nerve injury and neuropathic pain. Current Topics in Microbiology and Immunology. 2008. (In press)
52. Ik-Hyun Cho, Jinpyo Hong, Eun Cheng Suh, Eun-Kyeong Jo, Shizuo Akira , KyungEun Lee and Sung Joong Lee, Role of toll-like receptor 2 signaling in kainic acid-induced hippocampal neuronal cell death. 2009. (Manuscript in preparation)
BOOK CHAPTER
1. Soojin Lee and Sung Joong Lee, Toll-like receptors: sensor molecules for infection and tissue damage in the nervous system. Ch 5. Neuroimmunology Research Perspective, 2007, Nova Science Publishers Inc.
2. Kim D, Lee S, Lee SJ. Toll-like receptors in peripheral nerve injury and neuropathic pain. Current Topics in Microbiology and Immunology. 2008.
Copyright(c) 2003 BRIC, All rights reserved. Contact to part@bric.postech.ac.kr
 sungjoong.jpg (25.61KB, 1)
|
|
|
