ROCKs as immunomodulators of stroke

Expert Opinion on Therapeutic Targets

Volumn 16, Issue 10, 2012, Pages 1013-1025

  Wang, Qing Mei ^a   Liao, James K ^b  

^a and Red Sox Foundation and Massachusetts General Hospital Home Base Program   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Fasudil; Inflammation; Rho kinase; Stroke

Indexed keywords

CYTOKINE; FASUDIL; FINGOLIMOD; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INDOMETACIN; MINOCYCLINE; PLACEBO; RHO ASSOCIATED COILED COIL KINASE; RHO KINASE; RHO KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; BLEEDING; BRAIN HEMORRHAGE; BRAIN INFARCTION; BRAIN ISCHEMIA; BRAIN VASOSPASM; CELL DIFFERENTIATION; CELL FUNCTION; CYTOKINE PRODUCTION; DRUG TARGETING; ENDOTHELIUM CELL; ENZYME ACTIVITY; ENZYME INHIBITION; GRAFT REJECTION; HUMAN; HYPERTENSION; HYPOTENSION; IMMUNOMODULATION; INFLAMMATION; INFLAMMATORY CELL; LIVER TOXICITY; NERVE REGENERATION; NERVOUS SYSTEM DEVELOPMENT; NEUROPROTECTION; NEUTROPHIL; NONHUMAN; PROTEIN FUNCTION; PULMONARY HYPERTENSION; REVIEW; RISK FACTOR; SIGNAL TRANSDUCTION; SMOOTH MUSCLE CONTRACTION; STROKE; SUBARACHNOID HEMORRHAGE; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; THROMBOCYTE ACTIVATION; THROMBOCYTE FUNCTION; THROMBUS; VENOUS THROMBOEMBOLISM;

ANIMALS; HUMANS; IMMUNOLOGIC FACTORS; INFLAMMATION; INFLAMMATION MEDIATORS; RHO-ASSOCIATED KINASES; STROKE; T-LYMPHOCYTES;

EID: 84866505426     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2012.715149     Document Type: Review

References (140)

1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics-2011 update: a report from the American Heart Association. Circulation 2011;123(4):e18-e209
2. Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 2011;10(5):471-80
3. Noma K, Oyama N, Liao JK. Physiological role of ROCKs in the cardiovascular system. Am J Physiol Cell Physiol 2006;290(3):C661-8
4. Matsui T, Amano M, Yamamoto T, et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J 1996;15(9):2208-16 (Pubitemid 26141137)
5. Leung T, Chen XQ, Manser E, Lim L. The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol 1996;16(10):5313-27 (Pubitemid 26315050)
6. Higashi M, Shimokawa H, Hattori T, et al. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ Res 2003; 93(8):767-75 (Pubitemid 37288672)
7. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998; 273(37):24266-71 (Pubitemid 28435775)
8. Wolfrum S, Dendorfer A, Rikitake Y, et al. Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 2004;24(10):1842-7 (Pubitemid 39350301)
9. Endres M, Laufs U, Huang Z, et al. Stroke protection by 3-hydroxy-3- methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 1998;95(15):8880-5 (Pubitemid 28350583)
10. Liao JK, Seto M, Noma K. Rho kinase (ROCK) inhibitors. J Cardiovasc Pharmacol 2007; 50(1):17-24 (Pubitemid 47220442)
11. Masumoto A, Hirooka Y, Shimokawa H, et al. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension 2001; 38(6):1307-10 (Pubitemid 34033407)
12. Fukumoto Y, Matoba T, Ito A, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005; 91(3):391-2 (Pubitemid 40299237)
13. Shibuya M, Hirai S, Seto M, et al. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J Neurol Sci 2005;238(1-2):31-9 (Pubitemid 41560951)
14. Shibuya M, Suzuki Y, Sugita K, et al. Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial. J Neurosurg 1992;76(4):571-7
15. Masumoto A, Mohri M, Shimokawa H, et al. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002;105(13):1545-7 (Pubitemid 34297629)
16. Nakagawa O, Fujisawa K, Ishizaki T, et al. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 1996;392(2):189-93 (Pubitemid 26276745)
17. Shimizu Y, Thumkeo D, Keel J, et al. ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J Cell Biol 2005;168(6):941-53 (Pubitemid 40397008)
18. Thumkeo D, Keel J, Ishizaki T, et al. Targeted disruption of the mouse rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death. Mol Cell Biol 2003;23(14): 5043-55 (Pubitemid 36793348)
19. Noma K, Rikitake Y, Oyama N, et al. ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest 2008;118(5):1632-44 (Pubitemid 351632368)
20. Shimada H, Rajagopalan LE. Rho kinase-2 activation in human endothelial cells drives lysophosphatidic acid-mediated expression of cell adhesion molecules via NF-kappaB p65. J Biol Chem 2010;285(17):12536-42
21. Sodergren A, Stegmayr B, Ohman ML, Wallberg-Jonsson S. Increased incidence of stroke and impaired prognosis after stroke among patients with seropositive rheumatoid arthritis. Clin Exp Rheumatol 2009;27(4):641-4
22. Lindhardsen J, Ahlehoff O, Gislason GH, et al. Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. BMJ 2012;344:e1257
23. Futrell N, Millikan C. Frequency, etiology, and prevention of stroke in patients with systemic lupus erythematosus. Stroke 1989;20(5):583-91 (Pubitemid 19139084)
24. Bessant R, Hingorani A, Patel L, et al. Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 2004;43(7):924-9 (Pubitemid 38996970)
25. Elkind MS. Infectious burden: a new risk factor and treatment target for atherosclerosis. Infect Disord Drug Targets 2010;10(2):84-90
26. Emsley HC, Hopkins SJ. Acute ischaemic stroke and infection: recent and emerging concepts. Lancet Neurol 2008;7(4):341-53 (Pubitemid 351380535)
27. Stoll G, Kleinschnitz C, Nieswandt B. Combating innate inflammation: a new paradigm for acute treatment of stroke? Ann NY Acad Sci 2010;1207:149-54
28. Nieswandt B, Kleinschnitz C, Stoll G. Ischaemic stroke: a thrombo-inflammatory disease? J Physiol 2011;589(Pt 17):4115-23
29. Feske SK, Sorond FA, Henderson GV, et al. Increased leukocyte ROCK activity in patients after acute ischemic stroke. Brain Res 2009;1257:89-93
30. Amarenco P, Bogousslavsky J, Callahan A III, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355(6):549-59 (Pubitemid 44202151)
31. Endres M, Laufs U, Liao JK, Moskowitz MA. Targeting eNOS for stroke protection. Trends Neurosci 2004;27(5):283-9 (Pubitemid 38529957)
32. Sacco RL, Liao JK. Drug insight: statins and stroke. Nat Clin Pract Cardiovasc Med 2005;2(11):576-84 (Pubitemid 41655661)
33. Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360(18):1851-61
34. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343(6257):425-30
35. Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev 1997;11(18):2295-322 (Pubitemid 27408529)
36. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91(11):2844-50
37. Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 2008;112(9):3555-62
38. Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998;94(5):657-66 (Pubitemid 28427584)
39. De Meyer SF, Stoll G, Wagner DD, Kleinschnitz C. von Willebrand factor: an emerging target in stroke therapy. Stroke 2012;43(2):599-606
40. Folsom AR, Rosamond WD, Shahar E, et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation 1999; 100(7):736-42 (Pubitemid 29383644)
41. Tzoulaki I, Murray GD, Lee AJ, et al. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery Study. Circulation 2007;115(16):2119-27 (Pubitemid 46659063)
42. Kleinschnitz C, De Meyer SF, Schwarz T, et al. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood 2009;113(15):3600-3
43. Berndt MC, Shen Y, Dopheide SM, et al. The vascular biology of the glycoprotein Ib-IX-V complex. Thromb Haemost 2001;86(1):178-88 (Pubitemid 32663951)
44. Soriano SG, Coxon A, Wang YF, et al. Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/reperfusion injury. Stroke 1999;30(1):134-9 (Pubitemid 29029454)
45. Yang SA, Carpenter CL, Abrams CS. Rho and Rho-kinase mediate thrombin-induced phosphatidylinositol 4-phosphate 5-kinase trafficking in platelets. J Biol Chem 2004;279(40):42331-6 (Pubitemid 39313682)
46. Ono A, Westein E, Hsiao S, et al. Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth. Blood 2008;112(1):90-9
47. Leng L, Kashiwagi H, Ren XD, Shattil SJ. RhoA and the function of platelet integrin alphaIIbbeta3. Blood 1998;91(11):4206-15 (Pubitemid 28261984)
48. Shimada H, Rajagopalan LE. Rho-kinase mediates lysophosphatidic acid-induced IL-8 and MCP-1 production via p38 and JNK pathways in human endothelial cells. FEBS Lett 2010;584(13):2827-32
49. Akiyama N, Naruse K, Kobayashi Y, et al. High glucose-induced upregulation of Rho/Rho-kinase via platelet-derived growth factor receptor-beta increases migration of aortic smooth muscle cells. J Mol Cell Cardiol 2008;45(2):326-32
50. Hemmings DG, Hudson NK, Halliday D, et al. Sphingosine-1-phosphate acts via rho-associated kinase and nitric oxide to regulate human placental vascular tone. Biol Reprod 2006;74(1):88-94 (Pubitemid 43068794)
51. Mallat Z, Gojova A, Sauzeau V, et al. Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice. Circ Res 2003;93(9):884-8 (Pubitemid 37363063)
52. Wang HW, Liu PY, Oyama N, et al. Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice. FASEB J 2008;22(10):3561-70
53. Rekhter M, Chandrasekhar K, Gifford-Moore D, et al. Immunohistochemical analysis of target proteins of Rho-kinase in a mouse model of accelerated atherosclerosis. Exp Clin Cardiol 2007;12(4):169-74
54. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 1991;67(6):1033-6 (Pubitemid 121001517)
55. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76(2):301-14 (Pubitemid 24046692)
56. Mayadas TN, Johnson RC, Rayburn H, et al. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 1993;74(3):541-54 (Pubitemid 23244619)
57. Frenette PS, Mayadas TN, Rayburn H, et al. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell 1996;84(4):563-74 (Pubitemid 26071737)
58. Gavard J, Gutkind JS. Protein kinase C-related kinase and ROCK are required for thrombin-induced endothelial cell permeability downstream from Galpha12/13 and Galpha11/q. J Biol Chem 2008;283(44):29888-96
59. Sun H, Breslin JW, Zhu J, et al. Rho and ROCK signaling in VEGF-induced microvascular endothelial hyperpermeability. Microcirculation 2006;13(3):237-47
60. Breyer J, Samarin J, Rehm M, et al. Inhibition of Rho kinases increases directional motility of microvascular endothelial cells. Biochem Pharmacol 2012;83(5):616-26
61. Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 2003;17(8):905-7
62. Sauzeau V, Le Mellionnec E, Bertoglio J, et al. Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ Res 2001;88(11):1102-4 (Pubitemid 34132508)
63. Mack CP, Somlyo AV, Hautmann M, et al. Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization. J Biol Chem 2001;276(1):341-7 (Pubitemid 32050325)
64. Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 1997;389(6654):990-4 (Pubitemid 27485693)
65. Noma K, Goto C, Nishioka K, et al. Roles of rho-associated kinase and oxidative stress in the pathogenesis of aortic stiffness. J Am Coll Cardiol 2007;49(6):698-705 (Pubitemid 46205044)
66. Nohria A, Grunert ME, Rikitake Y, et al. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ Res 2006;99(12):1426-32 (Pubitemid 44949679)
67. Ding J, Li QY, Wang X, et al. Fasudil protects hippocampal neurons against hypoxia-reoxygenation injury by suppressing microglial inflammatory responses in mice. J Neurochem 2010;114(6):1619-29
68. Satoh S, Kobayashi T, Hitomi A, et al. Inhibition of neutrophil migration by a protein kinase inhibitor for the treatment of ischemic brain infarction. Jpn J Pharmacol 1999;80(1):41-8 (Pubitemid 29271512)
69. Magnus T, Wiendl H, Kleinschnitz C. Immune mechanisms of stroke. Curr Opin Neurol 2012;25(3):334-40
70. Weston RM, Jones NM, Jarrott B, Callaway JK. Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. J Cereb Blood Flow Metab 2007;27(1):100-14 (Pubitemid 46006588)
71. Price CJ, Menon DK, Peters AM, et al. Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study. Stroke 2004;35(7):1659-64 (Pubitemid 38823643)
72. Buck BH, Liebeskind DS, Saver JL, et al. Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke 2008;39(2):355-60 (Pubitemid 351619455)
73. Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 2011;10(12):826-37
74. Amantea D, Nappi G, Bernardi G, et al. Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 2009;276(1):13-26
75. Caso JR, Pradillo JM, Hurtado O, et al. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007;115(12):1599-608 (Pubitemid 46648645)
76. Lehnardt S, Lehmann S, Kaul D, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol 2007;190(1-2):28-33 (Pubitemid 47625604)
77. Zhang RL, Chopp M, Jiang N, et al. Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 1995;26(8):1438-42. discussion 43
78. Kitagawa K, Matsumoto M, Mabuchi T, et al. Deficiency of intercellular adhesion molecule 1 attenuates microcirculatory disturbance and infarction size in focal cerebral ischemia. J Cereb Blood Flow Metab 1998;18(12):1336-45 (Pubitemid 28559681)
79. Ishikawa M, Cooper D, Arumugam TV, et al. Platelet-leukocyte-endothelial cell interactions after middle cerebral artery occlusion and reperfusion. J Cereb Blood Flow Metab 2004;24(8):907-15 (Pubitemid 39045408)
80. Hayakawa K, Qiu J, Lo EH. Biphasic actions of HMGB1 signaling in inflammation and recovery after stroke. Ann N Y Acad Sci 2010;1207:50-7
81. Batchelor PE, Liberatore GT, Wong JY, et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 1999;19(5):1708-16 (Pubitemid 29094189)
82. Miwa T, Furukawa S, Nakajima K, et al. Lipopolysaccharide enhances synthesis of brain-derived neurotrophic factor in cultured rat microglia. J Neurosci Res 1997;50(6):1023-9 (Pubitemid 28034657)
83. Nakajima K, Kohsaka S. Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord 2004;4(1):65-84 (Pubitemid 38404716)
84. Ekdahl CT, Claasen JH, Bonde S, et al. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 2003;100(23):13632-7 (Pubitemid 37444791)
85. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003;302(5651):1760-5 (Pubitemid 37505739)
86. Liu Z, Fan Y, Won SJ, et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 2007;38(1):146-52 (Pubitemid 46035620)
87. Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M. Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 2005;29(3):381-93 (Pubitemid 40799211)
88. Kalluri HS, Vemuganti R, Dempsey RJ. Mechanism of insulin-like growth factor I-mediated proliferation of adult neural progenitor cells: role of Akt. Eur J Neurosci 2007;25(4):1041-8
89. Otaegi G, Yusta-Boyo MJ, Vergano-Vera E, et al. Modulation of the PI 3-kinase-Akt signalling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells. J Cell Sci 2006;119(Pt 13):2739-48 (Pubitemid 44184010)
90. Satoh S, Toshima Y, Hitomi A, et al. Wide therapeutic time window for Rho-kinase inhibition therapy in ischemic brain damage in a rat cerebral thrombosis model. Brain Res 2008;1193:102-8
91. Satoh S, Utsunomiya T, Tsurui K, et al. Pharmacological profile of hydroxy fasudil as a selective rho kinase inhibitor on ischemic brain damage. Life Sci 2001;69(12):1441-53 (Pubitemid 32758711)
92. Hara M, Takayasu M, Watanabe K, et al. Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats. J Neurosurg 2000;93(1 Suppl):94-101 (Pubitemid 30457388)
93. Arumugam TV, Granger DN, Mattson MP. Stroke and T-cells. Neuromolecular Med 2005;7(3):229-42 (Pubitemid 41507146)
94. Campanella M, Sciorati C, Tarozzo G, Beltramo M. Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke 2002;33(2):586-92 (Pubitemid 34123411)
95. Hurn PD, Subramanian S, Parker SM, et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab 2007;27(11):1798-805 (Pubitemid 47624547)
96. Wei Y, Yemisci M, Kim HH, et al. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol 2011; 69(1):119-29
97. Kipnis J, Yoles E, Porat Z, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci USA 2000;97(13):7446-51 (Pubitemid 30431483)
98. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008;112(5):1557-69
99. Vila N, Castillo J, Davalos A, et al. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke 2003;34(3):671-5 (Pubitemid 36307391)
100. Prehn JH, Bindokas VP, Marcuccilli CJ, et al. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons. Proc Natl Acad Sci USA 1994;91(26):12599-603
101. Kim ES, Kim RS, Ren RF, et al. Transforming growth factor-beta inhibits apoptosis induced by beta-amyloid peptide fragment 25-35 in cultured neuronal cells. Brain Res Mol Brain Res 1998;62(2):122-30 (Pubitemid 29010379)
102. Theodorou GL, Marousi S, Ellul J, et al. T helper 1 (Th1)/Th2 cytokine expression shift of peripheral blood CD4 + and CD8+ T cells in patients at the post-acute phase of stroke. Clin Exp Immunol 2008;152(3):456-63 (Pubitemid 351661501)
103. Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006;203(10):2271-9 (Pubitemid 44498362)
104. Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007;448(7152):484-7 (Pubitemid 47123515)
105. Fossiez F, Djossou O, Chomarat P, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 1996;183(6):2593-603 (Pubitemid 26193037)
106. Lighvani AA, Frucht DM, Jankovic D, et al. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci USA 2001;98(26):15137-42 (Pubitemid 34013982)
107. Rengarajan J, Szabo SJ, Glimcher LH. Transcriptional regulation of Th1/Th2 polarization. Immunol Today 2000;21(10):479-83
108. Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24(2):179-89 (Pubitemid 43214587)
109. Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441(7090):231-4
110. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441(7090):235-8
111. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature 2008;453(7198):1051-7 (Pubitemid 351871737)
112. Morishima N, Mizoguchi I, Takeda K, et al. TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23. Biochem Biophys Res Commun 2009;386(1):105-10
113. Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007;8(9):967-74 (Pubitemid 47300011)
114. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299(5609):1057-61 (Pubitemid 36222930)
115. Caplan S, Zeliger S, Wang L, Baniyash M. Cell-surface-expressed T-cell antigen-receptor zeta chain is associated with the cytoskeleton. Proc Natl Acad Sci USA 1995;92(11):4768-72
116. Rozdzial MM, Pleiman CM, Cambier JC, Finkel TH. pp56Lck mediates TCR zeta-chain binding to the microfilament cytoskeleton. J Immunol 1998;161(10):5491-9 (Pubitemid 28519112)
117. Tharaux PL, Bukoski RC, Rocha PN, et al. Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells. J Immunol 2003;171(1):96-105 (Pubitemid 36745277)
118. Teramoto H, Salem P, Robbins KC, et al. Tyrosine phosphorylation of the vav proto-oncogene product links FcepsilonRI to the Rac1-JNK pathway. J Biol Chem 1997;272(16):10751-5 (Pubitemid 27181087)
119. Perona R, Montaner S, Saniger L, et al. Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins. Genes Dev 1997;11(4):463-75 (Pubitemid 27097645)
120. Corre I, Gomez M, Vielkind S, Cantrell DA. Analysis of thymocyte development reveals that the GTPase RhoA is a positive regulator of T cell receptor responses in vivo. J Exp Med 2001;194(7):903-14
121. Schafer PH, Wadsworth SA, Wang L, Siekierka JJ. p38 alpha mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4 +CD45RO+ T cells and Th2 effector cells. J Immunol 1999;162(12):7110-19 (Pubitemid 29277680)
122. Koprak S, Staruch MJ, Dumont FJ. A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: dependence on CD28 signaling and preferential inhibition of IL-10 production. Cell Immunol 1999;192(2):87-95 (Pubitemid 29172074)
123. Biswas PS, Gupta S, Chang E, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest 2010;120(9):3280-95
124. Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 2010;87(5):779-89
125. Loddick SA, Rothwell NJ. Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 1996;16(5):932-40 (Pubitemid 26292060)
126. Stroemer RP, Rothwell NJ. Cortical protection by localized striatal injection of IL-1ra following cerebral ischemia in the rat. J Cereb Blood Flow Metab 1997;17(6):597-604 (Pubitemid 27306684)
127. Aloisi F. Immune function of microglia. Glia 2001;36(2):165-79 (Pubitemid 33055905)
128. Nakajima K, Kohsaka S. Microglia: activation and their significance in the central nervous system. J Biochem 2001;130(2):169-75 (Pubitemid 32785862)
129. Lambertsen KL, Clausen BH, Babcock AA, et al. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci 2009;29(5):1319-30
130. Tanaka R, Komine-Kobayashi M, Mochizuki H, et al. Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience 2003;117(3):531-9 (Pubitemid 36263149)
131. Schilling M, Strecker JK, Schabitz WR, et al. Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice. Neuroscience 2009;161(3):806-12
132. Petry KG, Boiziau C, Dousset V, Brochet B. Magnetic resonance imaging of human brain macrophage infiltration. Neurotherapeutics 2007;4(3):434-42 (Pubitemid 46962415)
133. Kleinschnitz C, Bendszus M, Frank M, et al. In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab 2003;23(11):1356-61 (Pubitemid 37409799)
134. Matoba K, Kawanami D, Ishizawa S, et al. Rho-kinase mediates TNF-alpha-induced MCP-1 expression via p38 MAPK signaling pathway in mesangial cells. Biochem Biophys Res Commun 2010;402(4):725-30
135. Blackburn D, Sargsyan S, Monk PN, Shaw PJ. Astrocyte function and role in motor neuron disease: a future therapeutic target? Glia 2009;57(12):1251-64
136. Lau CL, Perreau VM, Chen MJ, et al. Transcriptomic profiling of astrocytes treated with the Rho kinase inhibitor fasudil reveals cytoskeletal and pro-survival responses. J Cell Physiol 2012;227(3):1199-211
137. Lau CL, O'Shea RD, Broberg BV, et al. The Rho kinase inhibitor Fasudil up-regulates astrocytic glutamate transport subsequent to actin remodelling in murine cultured astrocytes. Br J Pharmacol 2011;163(3):533-45
138. Wei L, Roberts W, Wang L, et al. Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development 2001;128(15):2953-62 (Pubitemid 32771627)
139. Shin HK, Salomone S, Potts EM, et al. Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms. J Cereb Blood Flow Metab 2007;27(5):998-1009 (Pubitemid 46659030)
140. Rikitake Y, Kim HH, Huang Z, et al. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke 2005;36(10):2251-7 (Pubitemid 41429255)