Expression and localization of phospho-IkB in the central nervous system during experimental autoimmune encephalomyelitis in Lewis rats

자가면역성 뇌척수염 랫드의 중추신경계에서의 인산화된 IkB의 발현양상

  • Hwang, In Sun (Department of Veterinary Medicine, College of Agriculture and Life Science, Cheju National University) ;
  • Jee, Young Heun (Department of Veterinary Medicine, College of Agriculture and Life Science, Cheju National University)
  • 황인선 (제주대학교 농업생명과학대학 수의학과) ;
  • 지영흔 (제주대학교 농업생명과학대학 수의학과)
  • Accepted : 2005.01.12
  • Published : 2005.03.25


To elucidate the roles of phospho-IkB expression in the development and progression of EAE, we investigated the expression of phospho-IkB in the central nervous system (CNS) of rats during experimental autoimmune encephalomyelitis (EAE) using immunohistochemistry and Western blot analysis. In Western blot analysis, the increased expression of phospho-IkB went parallel to severity of EAE. The expression of phospho-IkB increased significantly at the peak stage of EAE followed by gradual decrease. Immunohistochemical studies showed that the phospho-IkB immunoreactivity was mainly expressed in inflammatory cells (macrophages, T cells) and glial cells (astrocytes, microglial cells) at the peak stage of EAE and disappeared at the recovery stage. These findings suggest that the phosphorylation of IkB is closely associated with autoimmune inflammation in the CNS and plays an important role in the initiation and progression of EAE.


Supported by : 한국과학재단


  1. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell 1996, 87, 13-20
  2. Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr. Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol Cell Biol 1993, 13, 3301-3310
  3. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 1995, 376, 167-170
  4. Greene WC, Bohnlein E, Ballard DW. HIV-1, HTLV-1 and normal T-cell growth: transcriptional strategies and surprises. Immunol Today 1989, 10, 272-278
  5. Grilli M, Chiu JJ, Lenardo MJ. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol 1993, 143, 1-62
  6. Henkel T, Machleidt T, Alkalay I, Kronke M, Ben-Neriah Y, Baeuerle PA. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature 1993, 365, 182-185
  7. Hilliard B, Samoilova EB, Liu TS, Rostami A, Chen Y. Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice: roles of NF-kappa B in the activation and differentiation of autoreactive T cells. J Immunol 1999, 163, 2937-2943
  8. O'Connor KC, Bar-Or A, Hafler DA. The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. J Clin Immunol 2001, 21, 81-92
  9. Olsson T. Critical influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol Rev 1995, 144, 245-268
  10. Raine CS. The Norton Lecture: a review of the oligodendrocyte in the multiple sclerosis lesion. J Neuroimmunol 1997, 77, 135-152
  11. Raine CS, Traugott U. Experimental autoimmune demyelination. Chronic relapsing models and their therapeutic implications for multiple sclerosis. Ann N Y Acad Sci 1984, 436, 33-51
  12. Shin T, Kojima T, Tanuma N, Ishihara Y, Matsumoto Y. The subarachnoid space as a site for precursor T cell proliferation and effector T cell selection in experimental autoimmune encephalomyelitis. J Neuroimmunol 1995, 56, 171-178
  13. Sun SC, Ganchi PA, Beraud C, Ballard DW, Greene WC. Autoregulation of the NF-kappa B transactivator RelA (p65) by multiple cytoplasmic inhibitors containing ankyrin motifs. Proc Natl Acad Sci USA 1994, 91, 1346-1350
  14. Thomas LH, Friedland JS, Sharland M, Becker S. Respiratory syncytial virus-induced RANTES production from human bronchial epithelial cells is dependent on nuclear factor-kappa B nuclear binding and is inhibited by adenovirus-mediated expression of inhibitor of kappa B alpha. J Immunol 1998, 161, 1007-1016
  15. Ting AT, Pimentel-Muinos FX, Seed B. RIP mediates tumor necrosis factor receptor 1 activation of NFkappaB but not Fas/APO-1-initiated apoptosis. EMBO J 1996, 15, 6189-6196
  16. Leppert D, Lindberg RL, Kappos L, Leib SL. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Res Brain Res Rev 2001, 36, 249-257
  17. Beg AA, Baltimore D. An essential role for NFkappaB in preventing TNF-alpha-induced cell death. Science 1996, 274, 782-784
  18. Brown K, Park S, Kanno T, Franzoso G, Siebenlist U. Mutual regulation of the transcriptional activator Nfkappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci USA 1993, 90, 2532-2536
  19. Liang Q, Bueno OF, Wilkins BJ, Kuan CY, Xia Y, Molkentin JD. c-Jun N-terminal kinases (JNK) antagonize cardiac growth through cross-talk with calcineurin-NFAT signaling. EMBO J 2003, 22, 5079-5089
  20. Chandler S, Miller KM, Clements JM, Lury J, Corkill D, Anthony DC, Adams SE, Gearing AJ. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J Neuroimmunol 1997, 72, 155-161
  21. Lenardo MJ, Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 1989, 58, 227-229
  22. Tsitoura DC, Rothman PB. Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells. J Clin Invest 2004, 113, 619-627
  23. Pahan K, Schmid M. Activation of nuclear factor-kB in the spinal cord of experimental allergic encephalomyelitis. Neurosci Lett 2000, 287, 17-20
  24. Steffen BJ, Butcher EC, Engelhardt B. Evidence for involvement of ICAM-1 and VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse. Am J Pathol 1994, 145, 189-201
  25. Wingren AG, Parra E, Varga M, Kalland T, Sjogren HO, Hedlund G, Dohlsten M. T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles. Crit Rev Immunol 1995, 15, 235-253
  26. Sha WC, Liou HC, Tuomanen EI, Baltimore D. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 1995, 80, 321-330
  27. Beg AA, Baldwin AS Jr. The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors. Genes Dev 1993, 7, 2064-2070
  28. Berg-Brown NN, Gronski MA, Jones RG, Elford AR, Deenick EK, Odermatt B, Littman DR, Ohashi PS. PKC{theta} Signals Activation versus Tolerance In Vivo. J Exp Med 2004, 199, 743-752
  29. Ishikawa H, Claudio E, Dambach D, Raventos-Suarez C, Ryan C, Bravo R. Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor (NF-kappaB1) but expressing p50. J Exp Med 1998, 187, 985-996
  30. Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 1997, 15, 707-747
  31. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997, 336, 1066-1071
  32. Liu SF, Ye X, Malik AB. In vivo inhibition of nuclear factor-kappa B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. J Immunol 1997, 159, 3976-3983
  33. Martin R, McFarland HF. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 1995, 32, 121-182
  34. Flores N, Duran C, Blasco MR, Puerta C, Dorado B, Garcia-Merino A, Ballester S. NFkappaB and AP-1 DNA binding activity in patients with multiple sclerosis. J Neuroimmunol 2003, 135, 141-147
  35. Merrill JE, Benveniste EN. Cytokines in inflammatory brain lesions: helpful and harmful. Trends Neurosci 1996, 19, 331-338
  36. Yang Y, Villain P, Mustelin T, Couture C. Critical role of Ser-520 phosphorylation for membrane recruitment and activation of the ZAP-70 tyrosine kinase in T cells. Mol Cell Biol 2003, 23, 7667-7677
  37. Sun SC, Ganchi PA, Ballard DW, Greene WC. Nfkappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science 1993, 259, 1912-1915
  38. Brocke S, Piercy C, Steinman L, Weissman IL, Veromaa T. Antibodies to CD44 and integrin alpha4, but not L-selectin, prevent central nervous system inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment. Proc Natl Acad Sci USA 1999, 96, 6896-6901
  39. Kuo CT, Leiden JM. Transcriptional regulation of T lymphocyte development and function. Annu Rev Immunol 1999, 17, 149-187