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Increased T cell Immunoglobulin and Mucin Domain 3 Positively Correlate with Systemic IL-17 and TNF-α Level in the Acute Phase of Ischemic Stroke

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Abstract

Tim-3 has been linked to several inflammatory diseases by regulation on both adaptive and innate immunities. Here, we assessed the augmented expression of Tim-3 in brain tissue of ischemia–reperfusion mice and PBMCs of ischemic stroke (IS) patients. The augmented expression of Tim-3 significantly correlated with abnormal lipid levels. In vitro studies showed that plasma from ischemic stroke patients induced Tim-3 expression in THP-1 cells. More importantly, our results revealed a significant correlation of Tim-3 expression on CD4+ T cells with systemic IL-17 in patients with ischemic stroke. Consistently, we also found a positive correlation of Tim-3 expression on CD14+ monocytes and serum TNF-α in IS patients. Collectively, augmented expression of Tim-3 may play an important role in the pathogenesis of ischemic stroke by regulation of proinflammatory cytokines. Further studies will give us new insights on the pathogenesis of ischemic stroke and potentially provide a new target at the medical therapy.

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References

  1. Hankey GJ. Stroke: how large a public health problem and how can the neurologist help? Arch Neurol. 1999;56(6):748–54.

    Article  PubMed  CAS  Google Scholar 

  2. Mitchell SV, Elkind, Tai W, Kristen C, Paik MC, Sacco RL. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med. 2006;166:2073–80.

    Article  Google Scholar 

  3. Nobuya I, Olga P, Reuhl KR, Oleg M. Inflammatory response and glutathione peroxidase in a model of stroke. J Immunol. 2002;168:1926–33.

    Google Scholar 

  4. Foulkes MA, Wolf PA, Price TR, Mohr JP, Hier DB. The Stroke Data Bank: design, methods, and baseline characteristics. Stroke. 1988;19:547–54.

    Article  PubMed  CAS  Google Scholar 

  5. Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006;26:654–65.

    Article  PubMed  CAS  Google Scholar 

  6. Vogelgesang A, Grunwald U, Langner S, Jack R, Bröker BM, Kessler C, et al. Analysis of lymphocyte subsets in patients with stroke and their influence on infection after stroke. Stroke. 2008;39:237–41.

    Article  PubMed  Google Scholar 

  7. Ross AM, Hurn P, Perrin N, Wood L, Carlini W, Potempa K. Evidence of the peripheral inflammatory response in patients with transient ischemic attack. J Stroke Cerebrovasc Dis. 2007;16:203–7.

    Article  PubMed  Google Scholar 

  8. Yang QW, Li JC, Lu FL, Wen AQ, Xiang J, Zhang LL, et al. Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. J Cereb Blood Flow Metab. 2008;28:1588–96.

    Article  PubMed  CAS  Google Scholar 

  9. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–41.

    Article  PubMed  CAS  Google Scholar 

  10. Kuchroo VK, Umetsu DT, DeKruyff RH, Freeman GJ. The TIM gene family: emerging roles in immunity and disease. Nat Rev Immunol. 2003;3:454–62.

    Article  PubMed  CAS  Google Scholar 

  11. Khademi M, Illés Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, et al. T cell Ig- and mucindomain- containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol. 2004;172:7169–76.

    PubMed  CAS  Google Scholar 

  12. Anderson AC, Anderson ED, Bregoli L, Hastings WD, Kassam N, Charles L, et al. Promotion of tissue inflammation by the immune receptor TIM-3 expressed on innate immune cells. Science. 2007;318:1141–3.

    Article  PubMed  CAS  Google Scholar 

  13. Sánchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol. 2003;4:1093–101.

    Article  PubMed  Google Scholar 

  14. Zhao J, Zhang L, Liu Y, Li B, Zhang L, Fang H, et al. Human pregnancy up-regulates Tim-3 in innate immune cells for systemic immunity. J Immunol. 2009;182:6618–24.

    Article  PubMed  CAS  Google Scholar 

  15. Yang G, Kitagawa K, Matsushita K, Mabuchi T, Yagita Y, Yanagihara T, et al. C57BL/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: selective neuronal death in the murine transient forebrain ischemia. Brain Res. 1997;752:209–18.

    Article  PubMed  CAS  Google Scholar 

  16. Fujii M, Hara H, Meng W, Vonsattel J, Huang Z, Moskowitz MA. Strain-related differences in susceptibility to transient forebrain ischemia in SV-129 and C57black/6 mice. Stroke. 1997;28:1805–11.

    Article  PubMed  CAS  Google Scholar 

  17. Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, et al. Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2008;67:63–70.

    Article  PubMed  CAS  Google Scholar 

  18. Vogelgesang A, May VE, Grunwald U, Bakkeboe M, Langner S, Wallaschofski H, et al. Functional status of peripheral blood T-cells in ischemic stroke patients. PLoS ONE. 2010;5:e8718.

    Article  PubMed  Google Scholar 

  19. Vila N, Castillo J, Dávalos A, Chamorro A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke. 2000;31:2325–9.

    Article  PubMed  CAS  Google Scholar 

  20. Vila N, Castillo J, Dávalos A, Esteve A, Planas AM, Chamorro A. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke. 2003;34:671–5.

    Article  PubMed  CAS  Google Scholar 

  21. Castellanos M, Castillo J, García MM, Leira R, Serena J, Chamorro A, et al. Inflammation-mediated damage in progressing lacunar infarctions: a potential therapeutic target. Stroke. 2002;33:982–7.

    Article  PubMed  Google Scholar 

  22. Chamorro A, Planas AM. Inflammation-mediated damage as a potential therapeutic target in acute ischemic stroke. Ernst Schering Res Found Worksho. 2004;47:185–204.

    CAS  Google Scholar 

  23. Frisancho-Kiss S, Nyland JF, Davis SE, Masheka V, Barrett, Gatewood SJL, et al. T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J Immunol. 2006;176:6411–5.

    PubMed  CAS  Google Scholar 

  24. Tziomalos K, Athyros VG, Karaqiannis A, Mikhailidis DP. Dyslipidemia as a risk factor for ischemic stroke. Curr Top Med Chem. 2009;9:1291–7.

    Article  PubMed  CAS  Google Scholar 

  25. Sierra-Johnson J, Somers VH, Kuniyoshi FH, Garza CA, Isley WL, Gami AS, et al. Comparison of apolipoprotein-B/apolipoprotein-A1 in subjects with versus without the metabolic syndrome. Am J Cardiol. 2006;98:1369–73.

    Article  PubMed  CAS  Google Scholar 

  26. Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med. 2002;8:1363–8.

    Article  PubMed  CAS  Google Scholar 

  27. Sotgiu S, Zanda B, Marchetti B, Fois ML, Arru G, Pes GM, et al. Inflammatory biomarkers in blood of patients with acute brain ischemia. Eur J Neurol. 2006;13:505–13.

    Article  PubMed  CAS  Google Scholar 

  28. Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, et al. Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke. 1997;28:1233–44.

    Article  PubMed  CAS  Google Scholar 

  29. Kostulas N, Pelidou SH, Kivisäkk P, Kostulas PV, Link H. Increased IL-1ß, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke. 1999;30:2174–9.

    Article  PubMed  CAS  Google Scholar 

  30. Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17-producing gammadelta T cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15:946–50.

    Article  PubMed  CAS  Google Scholar 

  31. Nakae S, Iwakura Y, Suto H, Galli SJ. Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. J Leukoc Biol. 2007;81:1258–68.

    Article  PubMed  CAS  Google Scholar 

  32. Li G-Z, Zhong D, Yang L-M, Sun B, Zhong Z-H, Yin Y-H, et al. Expression of interleukin-17 in ischemic brain tissue. Scand J Immuno. 2005;62:481–6.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by grants from the National Nature Science Foundation of China (no. 30972753) and the National Basic Research Program (no. 2009CB521900), Independent Innovation Foundation of Shandong University (IIFSDU), and Shandong Provincial Nature Science Foundation for Distinguished Young Scholars JQ200907.

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Authors and Affiliations

  1. Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Immunology, Shandong University School of Medicine, 44# Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Di Zhao, Nan Hou, Ying Liu, Xiaohong Liang, Lining Zhang, Lifen Gao & Chunhong Ma

  2. The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, 107# Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Yun Zhang

  3. Department of Physiology, Shandong University School of Medicine, 44# Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Min Cui

  4. Shandong University Qilu Hospital, 107# Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Xuewei Zhuang

  5. Jinan Central Hospital affiliated to Shandong University, 105# Jiefang Road, Jinan, Shandong, 250013, People’s Republic of China

    Yuanyuan Zhang

  6. Department of Pharmacology, College of Medicine, East Tennessee State University, Johnson City, TN, 37684, USA

    Deling Yin

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  1. Di Zhao
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  2. Nan Hou
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  3. Min Cui
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  8. Lining Zhang
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  10. Lifen Gao
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  11. Yun Zhang
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  12. Chunhong Ma
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Correspondence to Chunhong Ma.

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Zhao, D., Hou, N., Cui, M. et al. Increased T cell Immunoglobulin and Mucin Domain 3 Positively Correlate with Systemic IL-17 and TNF-α Level in the Acute Phase of Ischemic Stroke. J Clin Immunol 31, 719–727 (2011). https://doi.org/10.1007/s10875-011-9534-6

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  • DOI: https://doi.org/10.1007/s10875-011-9534-6

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