Ambivalent aspects of interleukin-6 in cerebral ischemia: Inflammatory versus neurotrophic aspects

Journal of Cerebral Blood Flow and Metabolism

Volumn 29, Issue 3, 2009, Pages 464-479

  Suzuki, Shigeaki ^a   Tanaka, Kortaro ^b   Suzuki, Norihiro ^a  

^a KEIO UNIVERSITY   (Japan)

^b TOYAMA UNIVERSITY HOSPITAL   (Japan)

Author keywords

Cerebral ischemia; Interleukin 6; JAK STAT; Leukemia inhibitory factor; Neuron; Stat3

Indexed keywords

CILIARY NEUROTROPHIC FACTOR; CILIARY NEUROTROPHIC FACTOR RECEPTOR ALPHA; CYTOKINE RECEPTOR; GLYCOPROTEIN GP 130; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR ALPHA; JANUS KINASE; LEUKEMIA INHIBITORY FACTOR; STAT PROTEIN; STAT3 PROTEIN;

ATHEROSCLEROSIS; BLOOD LEVEL; BRAIN INJURY; BRAIN ISCHEMIA; BRAIN NERVE CELL; BRAIN REGION; CENTRAL NERVOUS SYSTEM DISEASE; CEREBROVASCULAR ACCIDENT; DOWNSTREAM PROCESSING; GENETIC POLYMORPHISM; HUMAN; INFLAMMATION; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REPERFUSION; REVIEW; STROKE;

ANIMALS; BRAIN ISCHEMIA; CILIARY NEUROTROPHIC FACTOR; HUMANS; INTERLEUKIN-6; LEUKEMIA INHIBITORY FACTOR; NEURONS; PHOSPHORYLATION; POLYMORPHISM, GENETIC; STAT3 TRANSCRIPTION FACTOR;

EID: 61349130664     PISSN: 0271678X     EISSN: None     Source Type: Journal    
DOI: 10.1038/jcbfm.2008.141     Document Type: Review

References (125)

1. Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffarth GU, Grau AJ, Green FR, Grond-Ginsbach C, Schwaninger M (2003) Multiple levels of regulation of the interleukin-6 system in stroke. Stroke 34:1864-9
2. Akira S, Taga T, Kishimoto T (1993) Interleukin-6 in biology and medicine. Adv Immunol 54:1-78
3. Ali C, Nicole O, Docagne F, Lesne S, MacKenzie ET, Nouvelot A, Buisson A, Vivien D (2000) Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain. J Cereb Blood Flow Metab 20:956-66
4. Balding J, Livingstone WJ, Pittock SJ, Mynett-Johnson L, Ahern T, Hodgson A, Smith OP (2004) The IL-6 G-174C polymorphism may be associated with ischaemic stroke in patients without a history of hypertension. Ir J Med Sci 173:200-3
5. Banner LR, Moayeri NN, Patterson PH (1997) Leukemia inhibitory factor is expressed in astrocytes following cortical brain injury. Exp Neurol 147:1-9
6. Barone FC, Feuerstein GZ (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:819-34
7. Basso F, Lowe GD, Rumley A, McMahon AD, Humphries SE (2002) Interleukin-6 -174G > C polymorphism and risk of coronary heart disease in West of Scotland coronary prevention study (WOSCOPS). Arterioscler Thromb Vasc Biol 22:599-604
8. Battle TE, Frank DA (2002) The role of STATs in apoptosis. Curr Mol Med 2:381-92
9. Bauer S, Rasika S, Han J, Mauduit C, Raccurt M, Morel G, Jourdan F, Benahmed M, Moyse E, Patterson PH (2003) Leukemia inhibitory factor is a key signal for injury-induced neurogenesis in the adult mouse olfactory epithelium. J Neurosci 23:1792-803
10. Beamer NB, Coull BM, Clark WM, Hazel JS, Silberger JR (1995) Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol 37:800-5
11. Blesch A, Uy HS, Grill RJ, Cheng JG, Patterson PH, Tuszynski MH (1999) Leukemia inhibitory factor augments neurotrophin expression and corticospinal axon growth after adult CNS injury. J Neurosci 19: 3556-66
12. Block F, Peters M, Nolden-Koch M (2000) Expression of IL-6 in the ischemic penumbra. Neuroreport 11:963-7
13. Butzkueven H, Zhang JG, Soilu-Hanninen M, Hochrein H, Chionh F, Shipham KA, Emery B, Turnley AM, Petratos S, Ernst M, Bartlett PF, Kilpatrick TJ (2002) LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 8:613-9
14. Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC (1999) Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol 163:3963-8
15. Cattaneo E, Conti L, De-Fraja C (1999) Signalling through the JAK-STAT pathway in the developing brain. Trends Neurosci 22:365-9
16. Chamorro A, Revilla M, Obach V, Vargas M, Planas AM (2005) The -174G/C polymorphism of the interleukin 6 gene is a hallmark of lacunar stroke and not other ischemic stroke phenotypes. Cerebrovasc Dis 19:91-5
17. Chai Z, Gatti S, Toniatti C, Poli V, Bartfai T (1996) Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice. J Exp Med 183:311-6
18. Chiang CS, Stalder A, Samimi A, Campbell IL (1994) Reactive gliosis as a consequence of interleukin-6 expression in the brain: studies in transgenic mice. Dev Neurosci 16:212-21
19. Choi JS, Kim SY, Cha JH, Choi YS, Sung KW, Oh ST, Kim ON, Chung JW, Chun MH, Lee SB, Lee MY (2003) Upregulation of gp130 and STAT3 activation in the rat hippocampus following transient forebrain ischemia. Glia 41:237-46
20. Clark WM, Rinker LG, Lessov NS, Hazel K, Hill JK, Stenzel-Poore M, Eckenstein F (2000) Lack of interleukin-6 expression is not protective against focal central nervous system ischemia. Stroke 31:1715-20
21. Covey MV, Levison SW (2007) Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia. Neuroscience 148:501-9
22. DeGraba TJ (1998) The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy. Neurology 51:S62-8
23. Dihne M, Peters M, Block F (2001) Interleukin-6 expression in exo-focal neurons after striatal cerebral ischemia. Neuroreport 12:3143-8
24. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391-7
25. Dziennis S, Jia T, Ronnekleiv OK, Hurn PD, Alkayed NJ (2007) Role of signal transducer and activator of transcription-3 in estradiol-mediated neuroprotection. J Neurosci 27:7268-74
26. Fan Y, Ye J, Shen F, Zhu Y, Yeghiazarians Y, Zhu W, Chen Y, Lawton MT, Young WL, Yang GY (2008) Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro. J Cereb Blood Flow Metab 28:90-8
27. Fassbender K, Rossol S, Kammer T, Daffertshofer M, Wirth S, Dollman M, Hennerici M (1994) Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease. J Neurol Sci 122:135-9
28. Ferrarese C, Mascarucci P, Zoia C, Cavarretta R, Frigo M, Begni B, Sarinella F, Frattola L, De Simoni MG (1999) Increased cytokine release from peripheral blood cells after acute stroke. J Cereb Blood Flow Metab 19:1004-9
29. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369-76
30. Flex A, Gaetani E, Papaleo P, Straface G, Proia AS, Pecorini G, Tondi P, Pola P, Pola R (2004) Proinflammatory genetic profiles in subjects with history of ischemic stroke. Stroke 35:2270-5
31. Gladilin S, Bidmon HJ, Divanach A, Arteel GE, Witte OW, Zilles K, Sies H (2000) Ebselen lowers plasma interleukin-6 levels and glial heme oxygenase-1 expression after focal photothrombotic brain ischemia. Arch Biochem Biophys 380:237-42
32. Grocott HP, White WD, Morris RW, Podgoreanu MV, Mathew JP, Nielsen DM, Schwinn DA, Newman MF (2005) Genetic polymorphisms and the risk of stroke after cardiac surgery. Stroke 36:1854-8
33. Gu F, Hata R, Ma YJ, Tanaka J, Mitsuda N, Kumon Y, Hanakawa Y, Hashimoto K, Nakajima K, Sakanaka M (2005) Suppression of Stat3 promotes neurogenesis in cultured neural stem cells. J Neurosci Res 81:163-71
34. Haas CA, Hofmann HD, Kirsch M (1999) Expression of CNTF/LIF-receptor components and activation of STAT3 signaling in axotomized facial motoneurons: evidence for a sequential postlesional function of the cytokines. J Neurobiol 41:559-71
35. Hallenbeck JM (2002) The many faces of tumor necrosis factor in stroke. Nat Med 8:1363-8
36. Hama T, Kushima Y, Miyamoto M, Kubota M, Takei N, Hatanaka H (1991) Interleukin-6 improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from postnatal, two-week-old rats in cultures. Neuroscience 40:445-52
37. Hans VH, Kossmann T, Lenzlinger PM, Probstmeier R, Imhof HG, Trentz O, Morganti-Kossmann MC (1999) Experimental axonal injury triggers interleukin-6 mRNA, protein synthesis and release into cerebrospinal fluid. J Cereb Blood Flow Metab 19:184-94
38. Hatta T, Moriyama K, Nakashima K, Taga T, Otani H (2002) The Role of gp130 in cerebral cortical development: in vivo functional analysis in a mouse exo utero system. J Neurosci 22:5516-24
39. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1-20
40. Hermann DM, Kilic E, Kugler S, Isenmann S, Bahr M (2001) Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiol Dis 8:655-66
41. Herrmann O, Tarabin V, Suzuki S, Attigah N, Coserea I, Schneider A, Vogel J, Prinz S, Schwab S, Monyer H, Brombacher F, Schwaninger M (2003) Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia. J Cereb Blood Flow Metab 23:406-15
42. Hill JK, Gunion-Rinker L, Kulhanek D, Lessov N, Kim S, Clark WM, Dixon MP, Nishi R, Stenzel-Poore MP, Eckenstein FP (1999) Temporal modulation of cytokine expression following focal cerebral ischemia in mice. Brain Res 820:45-54
43. Hilton DJ (1992) LIF: lots of interesting functions. Trends Biochem Sci 17:72-6
44. Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183:2627-34
45. Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66:232-45
46. Iadecola C, Alexander M (2001) Cerebral ischemia and inflammation. Curr Opin Neurol 14:89-94
47. Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y (2001) Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 32:1208-15
48. Jenny NS, Tracy RP, Ogg MS, Luong le A, Kuller LH, Arnold AM, Sharrett AR, Humphries SE (2002) In the elderly, interleukin-6 plasma levels and the -174G > C polymorphism are associated with the development of cardiovascular disease. Arterioscler Thromb Vasc Biol 22:2066-71
49. Justicia C, Gabriel C, Planas AM (2000) Activation of the JAK/STAT pathway following transient focal cerebral ischemia: signaling through Jak1 and Stat3 in astrocytes. Glia 30:253-70
50. Karahan ZC, Deda G, Sipahi T, Elhan AH, Akar N (2005) TNF-alpha -308G/A and IL-6 -174 G/C polymorphisms in the Turkish pediatric stroke patients. Thromb Res 115:393-8
51. Kharazmi A, Nielsen H, Rechnitzer C, Bendtzen K (1989) Interleukin 6 primes human neutrophil and monocyte oxidative burst response. Immunol Lett 21:177-84
52. Kim SY, Park HJ, Choi JS, Lee JE, Cha JH, Choi YS, Cho KO, Chun MH, Lee MY (2004) Ischemic preconditioning-induced expression of gp130 and STAT3 in astrocytes of the rat hippocampus. Brain Res Mol Brain Res 129:96-103
53. Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, Mochizuki H, Mizuno Y, Urabe T (2006) Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 26:402-13
54. Kumon Y, Sakaki S, Watanabe H, Nakano K, Ohta S, Matsuda S, Yoshimura H, Sakanaka M (1996) Ciliary neurotrophic factor attenuates spatial cognition impairment, cortical infarction and thalamic degeneration in spontaneously hypertensive rats with focal cerebral ischemia. Neurosci Lett 206:141-4
55. Lalouschek W, Schillinger M, Hsieh K, Endler G, Greisenegger S, Marculescu R, Lang W, Wagner O, Cheng S, Mannhalter C (2006) Polymorphisms of the inflammatory system and risk of ischemic cerebrovascular events. Clin Chem Lab Med 44:918-23
56. Legos JJ, Whitmore RG, Erhardt JA, Parsons AA, Tuma RF, Barone FC (2000) Quantitative changes in interleukin proteins following focal stroke in the rat. Neurosci Lett 282:189-92
57. Lemke R, Gadient RA, Patterson PH, Bigl V, Schliebs R (1997) Leukemia inhibitory factor (LIF) mRNA-expressing neuronal subpopulations in adult rat basal forebrain. Neurosci Lett 229:69-71
58. Lemke R, Hartig W, Rossner S, Bigl V, Schliebs R (1998) Interleukin-6 is not expressed in activated microglia and in reactive astrocytes in response to lesion of rat basal forebrain cholinergic system as demonstrated by combined in situ hybridization and immunocytochemistry. J Neurosci Res 51:223-36
59. Lemoli RM, Cavo M, Fortuna A (1996) Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of patients with multiple myeloma. J Hematother 5:339-49
60. Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135-43
61. Lin TN, Wang PY, Chi SI, Kuo JS (1998) Differential regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor alpha (CNTFR alpha) expression following focal cerebral ischemia. Brain Res Mol Brain Res 55:71-80
62. Loddick SA, Turnbull AV, Rothwell NJ (1998) Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 18:176-9
63. Londreth GE (1999) Growth factors. In: Basic Neurochemistry (Siegel GJ, ed), Philadelphia: Lippincott-Raven, 383-98
64. Maeda Y, Matsumoto M, Hori O, Kuwabara K, Ogawa S, Yan SD, Ohtsuki T, Kinoshita T, Kamada T, Stern DM (1994) Hypoxia/reoxygenation-mediated induction of astrocyte interleukin 6: a paracrine mechanism potentially enhancing neuron survival. J Exp Med 180:2297-308
65. Matsuda S, Wen TC, Morita F, Otsuka H, Igase K, Yoshimura H, Sakanaka M (1996) Interleukin-6 prevents ischemia-induced learning disability and neuronal and synaptic loss in gerbils. Neurosci Lett 204:109-12
66. Minami M, Kuraishi Y, Satoh M (1991) Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain. Biochem Biophys Res Commun 176:593-8
67. Morikawa Y, Tohya K, Tamura S, Ichihara M, Miyajima A, Senba E (2000) Expression of interleukin-6 receptor, leukemia inhibitory factor receptor and glycoprotein 130 in the murine cerebellum and neuropathological effect of leukemia inhibitory factor on cerebellar Purkinje cells. Neuroscience 100:841-8
68. Muir KW, Tyrrell P, Sattar N, Warburton E (2007) Inflammation and ischaemic stroke. Curr Opin Neurol 20:334-42
69. Murphy PG, Borthwick LS, Johnston RS, Kuchel G, Richardson PM (1999) Nature of the retrograde signal from injured nerves that induces interleukin-6 mRNA in neurons. J Neurosci 19:3791-800
70. Ogata N, Ogata K, Imhof HG, Yonekawa Y (1996) Effect of CNTF on ischaemic cell damage in rat hippocampus. Acta Neurochir (Wien) 138:580-3
71. Orzylowska O, Oderfeld-Nowak B, Zaremba M, Januszewski S, Mossakowski M (1999) Prolonged and concomitant induction of astroglial immunoreactivity of interleukin-1beta and interleukin-6 in the rat hippocampus after transient global ischemia. Neurosci Lett 263:72-6
72. Park CK, Ju WK, Hofmann HD, Kirsch M, Ki Kang J, Chun MH, Lee MY (2000) Differential regulation of ciliary neurotrophic factor and its receptor in the rat hippocampus following transient global ischemia. Brain Res 861:345-53
73. Penkowa M, Moos T, Carrasco J, Hadberg H, Molinero A, Bluethmann H, Hidalgo J (1999) Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice. Glia 25:343-57
74. Planas AM, Gorina R, Chamorro A (2006) Signalling pathways mediating inflammatory responses in brain ischaemia. Biochem Soc Trans 34:1267-70
75. Planas AM, Soriano MA, Berruezo M, Justicia C, Estrada A, Pitarch S, Ferrer I (1996) Induction of Stat3, a signal transducer and transcription factor, in reactive microglia following transient focal cerebral ischaemia. Eur J Neurosci 8:2612-8
76. Prudhomme JG, Sherman IW, Land KM, Moses AV, Stenglein S, Nelson JA (1996) Studies of Plasmodium falciparum cytoadherence using immortalized human brain capillary endothelial cells. Int J Parasitol 26: 647-55
77. Raghavendra Rao VL, Bowen KK, Dhodda VK, Song G, Franklin JL, Gavva NR, Dempsey RJ (2002) Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. J Neurochem 83:1072-86
78. Rauramaa R, Vaisanen SB, Luong LA, Schmidt-Trucksass A, Penttila IM, Bouchard C, Toyry J, Humphries SE (2000) Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis. Arterioscler Thromb Vasc Biol 20:2657-62
79. Reyes TM, Fabry Z, Coe CL (1999) Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli. Brain Res 851:215-20
80. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767-72
81. Rödel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsasser HP, Moroy T (2000) The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3. EMBO J 19:5845-55
82. Saito K, Suyama K, Nishida K, Sei Y, Basile AS (1996) Early increases in TNF-alpha, IL-6 and IL-1 beta levels following transient cerebral ischemia in gerbil brain. Neurosci Lett 206:149-52
83. Sallmann S, Juttler E, Prinz S, Petersen N, Knopf U, Weiser T, Schwaninger M (2000) Induction of interleukin-6 by depolarization of neurons. J Neurosci 20:8637-42
84. Satriotomo I, Bowen KK, Vemuganti R (2006) JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. J Neurochem 98:1353-68
85. Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S (2003) Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34:745-51
86. Schiefer J, Topper R, Schmidt W, Block F, Heinrich PC, Noth J, Schwarz M (1998) Expression of interleukin 6 in the rat striatum following stereotaxic injection of quinolinic acid. J Neuroimmunol 89:168-76
87. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H (2000) Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 101:1372-8
88. Scholzke MN, Schwaninger M (2007) Transcriptional regulation of neurogenesis: potential mechanisms in cerebral ischemia. J Mol Med 85:577-88
89. Schwaninger M, Neher M, Viegas E, Schneider A, Spranger M (1997) Stimulation of interleukin-6 secretion and gene transcription in primary astrocytes by adenosine. J Neurochem 69:1145-50
90. Sharp FR, Lu A, Tang Y, Millhorn DE (2000) Multiple molecular penumbras after focal cerebral ischemia. J Cereb Blood Flow Metab 20:1011-32
91. Shimazaki T, Shingo T, Weiss S (2001) The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. J Neurosci 21:7642-53
92. Shioda S, Ozawa H, Dohi K, Mizushima H, Matsumoto K, Nakajo S, Takaki A, Zhou CJ, Nakai Y, Arimura A (1998) PACAP protects hippocampal neurons against apoptosis: involvement of JNK/SAPK signaling pathway. Ann NY Acad Sci 865:111-7
93. Shyu WC, Lin SZ, Chiang MF, Chen DC, Su CY, Wang HJ, Liu RS, Tsai CH, Li H (2008) Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/ Stat3 pathway in murine models of stroke. J Clin Invest 118:133-48
94. Slevin M, Krupinski J, Mitsios N, Perikleous C, Cuadrado E, Montaner J, Sanfeliu C, Luque A, Kumar S, Kumar P, Gaffney J (2008) Leukaemia inhibitory factor is overexpressed by ischaemic brain tissue concomitant with reduced plasma expression following acute stroke. Eur J Neurol 15:29-37
95. Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM, del Zoppo GJ, Hallenbeck JM, Rothwell NJ, Hopkins SJ, Tyrrell PJ (2004) Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 4:2
96. Sriram K, Benkovic SA, Hebert MA, Miller DB, O'Callaghan JP (2004) Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem 279:19936-47
97. Stromberg H, Svensson SP, Hermanson O (2000) Distribution of the transcription factor signal transducer and activator of transcription 3 in the rat central nervous system and dorsal root ganglia. Brain Res 853:105-14
98. Suzuki S, Tanaka K, Nogawa S, Nagata E, Ito D, Dembo T, Fukuuchi Y (1999a) Temporal profile and cellular localization of interleukin-6 protein after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 19:1256-62
99. Suzuki S, Tanaka K, Nagata E, Ito D, Dembo T, Fukuuchi Y (1999b) Cerebral neurons express interleukin-6 after transient forebrain ischemia in gerbils. Neurosci Lett 262:117-20
100. Suzuki S, Tanaka K, Nogawa S, Ito D, Dembo T, Kosakai A, Fukuuchi Y (2000a) Immunohistochemical detection of leukemia inhibitory factor after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 20:661-8
101. Suzuki S, Tanaka K, Nogawa S, Dembo T, Kosakai A, Fukuuchi Y (2000b) Expression of interleukin-6 is suppressed by inhibition of voltage-sensitive Na+/ Ca2+ channels after cerebral ischemia. Neuroreport 11:2565-9
102. Suzuki S, Tanaka K, Nogawa S, Dembo T, Kosakai A, Fukuuchi Y (2001) Phosphorylation of signal transducer and activator of transcription-3 (Stat3) after focal cerebral ischemia in rats. Exp Neurol 170:63-71
103. Suzuki S, Tanaka K, Nogawa S, Umezawa A, Hata J, Fukuuchi Y (2002) Expression of interleukin-6 in cerebral neurons and ovarian cancer tissue in Trousseau syndrome. Clin Neuropathol 21:232-5
104. Suzuki S, Yamashita T, Tanaka K, Hattori H, Sawamoto K, Okano H, Suzuki N (2005) Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuates ischemic brain injury in rats. J Cereb Blood Flow Metab 25:685-93
105. Swartz KR, Liu F, Sewell D, Schochet T, Campbell I, Sandor M, Fabry Z (2001) Interleukin-6 promotes posttraumatic healing in the central nervous system. Brain Res 896:86-95
106. Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797-819
107. Tanaka K (2001) Alteration of second messengers during acute cerebral ischemia-adenylate cyclase, cyclic AMP-dependent protein kinase, and cyclic AMP response element binding protein. Prog Neurobiol 65:173-207
108. Tanaka K, Nogawa S, Ito D, Suzuki S, Dembo T, Kosakai A, Fukuuchi Y (2001) Phosphorylation of cyclic adenosine monophosphate response element binding protein in oligodendrocytes in the corpus callosum after focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 21:1177-88
109. Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, Tarkowski A (1995) Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke 26:1393-8
110. Toulmond S, Vige X, Fage D, Benavides J (1992) Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neurosci Lett 144:49-52
111. Tso AR, Merino JG, Warach S (2007) Interleukin-6 174G/C polymorphism and ischemic stroke: a systematic review. Stroke 38:3070-5
112. Van Wagoner NJ, Benveniste EN (1999) Interleukin-6 expression and regulation in astrocytes. J Neuroimmunol 100:124-39
113. Vila N, Castillo J, Davalos A, Chamorro A (2000) Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31:2325-9
114. Vollenweider F, Herrmann M, Otten U, Nitsch C (2003) Interleukin-6 receptor expression and localization after transient global ischemia in gerbil hippocampus. Neurosci Lett 341:49-52
115. Waje-Andreassen U, Krakenes J, Ulvestad E, Thomassen L, Myhr KM, Aarseth J, Vedeler CA (2005) IL-6: an early marker for outcome in acute ischemic stroke. Acta Neurol Scand 111:360-5
116. Wang X, Yue TL, Young PR, Barone FC, Feuerstein GZ (1995) Expression of interleukin-6, c-fos, and zif268 mRNAs in rat ischemic cortex. J Cereb Blood Flow Metab 15:166-71
117. Watanabe D, Yoshimura R, Khalil M, Yoshida K, Kishimoto T, Taga T, Kiyama H (1996) Characteristic localization of gp130 (the signal-transducing receptor component used in common for IL-6/IL-11/CNTF/LIF/OSM) in the rat brain. Eur J Neurosci 8:1630-40
118. Weger M, Steinbrugger I, Haas A, Marz W, El-Shabrawi Y, Weger W, Schmut O, Renner W (2005) Role of the interleukin-6 -174 G > C gene polymorphism in retinal artery occlusion. Stroke 36:249-52
119. Wen TC, Peng H, Hata R, Desaki J, Sakanaka M (2001) Induction of phosphorylated-Stat3 following focal cerebral ischemia in mice. Neurosci Lett 303: 153-6
120. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101:311-20
121. Yamada M, Hatanaka H (1994) Interleukin-6 protects cultured rat hippocampal neurons against glutamate-induced cell death. Brain Res 643:173-80
122. Yamagami H, Kitagawa K, Nagai Y, Hougaku H, Sakaguchi M, Kuwabara K, Kondo K, Masuyama T, Matsumoto M, Hori M (2004) Higher levels of interleukin-6 are associated with lower echogenicity of carotid artery plaques. Stroke 35:677-81
123. Yamakuni H, Minami M, Satoh M (1996) Localization of mRNA for leukemia inhibitory factor receptor in the adult rat brain. J Neuroimmunol 70:45-53
124. Yamashita T, Sawamoto K, Suzuki S, Suzuki N, Adachi K, Kawase T, Mihara M, Ohsugi Y, Abe K, Okano H (2005) Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem 94:459-68
125. Yi JH, Park SW, Kapadia R, Vemuganti R (2007) Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage. Neurochem Int 50:1014-27