GITR/GITRL信号通路与支气管哮喘的研究进展
Recent Advance in GITR/GITRL Signaling Pathway and Bronchial Asthma
DOI: 10.12677/ACRP.2013.12006, PDF, HTML, XML, 下载: 3,346  浏览: 16,597 
作者: 应亚萍, 金小红, 姚泽忠:温州医学院附属台州医院儿科;童夏生:台州市中西医结合医院儿科
关键词: GITRGITRL支气管哮喘GITR; GITRL; Bronchial Asthma
摘要: 本文采用基于密度泛函理论(DFT)框架下广义梯度近似平面波超软赝势法,支气管哮喘是一种全球性的发病率日益升高的呼吸道变应性疾病,支气管哮喘严重影响儿童的生长发育和心理健康,甚至威胁到他们的生命。但其发病机制目前尚未完全阐明,传统的观点认为Th1/Th2平衡失调理论在哮喘的发病中起着重要的作用。但随着对Th1,Th2以外的其他T细胞亚群的研究,人们逐渐发现CD4+CD25+Treg细胞与哮喘有着密切的关系。而糖皮质激素诱导的肿瘤坏死因子受体(Glucocorticoid-induced tumor necrosis factor receptor GITR)是属于肿瘤坏死因子受体(Tumor necrosis factor receptor TNFR)超家族的成员之一,在CD4+CD25+T调节细胞(Regulatory T cell Treg)细胞高表达,与其配体糖皮质激素诱导的肿瘤坏死因子受体配体(Glucocorticoid-induced tumor necrosis factor receptor ligand GITRL)结合后能增强T细胞激活、增殖、分泌细胞因子、MAPKs和NF-κB激活效应、抑制CD4+CD25+Treg细胞的功能,从而加强效应性T细胞的活性,有利于增强抗肿瘤免疫和抗病毒免疫,在免疫系统的调节中起着复杂的作用。
Abstract: Bronchial asthma is a global respiratory allergic disease, with the rising incidence of bronchial asthma in children. It has seriously affected children’s growth and mental health, and even may be life-threatening. But its pathogenesis has not fully elucidated so far, and the traditional view is that the disorder of Th1/Th2 balance plays an important role in the onset of asthma. But with the study of other T cell subsets besides Th1 and Th2, we gradually find that there exists a close relationgship between CD4+CD25+ Regulatory T cell (Treg) and asthma. Glucocorticoid-induc- ed tumor necrosis factor receptor (GITR) is one member of Tumor necrosis factor receptor (TNFR) superfamily, and is highly expressed in CD4+CD25+ Treg. When combining with its ligand GITRL (Glucocorticoid-induced tumor necrosis factor receptor ligand). They can not only enhance the activation and proliferation of T cell, enhance the effect of MAPKs and NF-κB, but also inhibit the function of CD4+CD25+ Treg cells. GITR/GITRL signal is beneficial to antitumor immune and antiviral immunity and plays a complex role in the regulation of the immune system.
文章引用:应亚萍, 童夏生, 金小红, 姚泽忠. GITR/GITRL信号通路与支气管哮喘的研究进展[J]. 亚洲儿科病例研究, 2013, 1(2): 23-29. http://dx.doi.org/10.12677/ACRP.2013.12006

参考文献

[1] J. E. Nichols. Human lymphocyte apoptosis after exposure to an influenza A virus. Journal of Virology, 2001, 75(13): 5921-5929.
[2] L. M. Snell, G. H. Lin, A. J. McPherson, et al. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer im- munotherapy. Immunological Reviews, 2011, 244(1): 197-217.
[3] E. C. Shin, J. S. Shin, J. H. Park, et al. Expression of Fasligand in hunman hepatan a cell lines role of hepatitis-B virus (HBX) in induction of Fasligand. International Journal of Cancer, 1999, 82(4): 587-591.
[4] G. P. Garlet, C. R. Cardoso, F. S. Mariano, et al. Regulatory T cells attenuate experimental periodontitis progression in mice. Journal of Clinical Periodontology, 2010, 37(7): 591-560.
[5] G. Nocentini, C. Riccardi, et al. GITR: A modulator of immune response and inflammation. Advances in Experimental Medicine and Biology, 2009, 647(10): 156-173.
[6] M. Azuma. Role of the glucocorticoid-induced TNFR-related protein (GITR)-GITR ligand pathway in innate and adaptive immunity. Immunology, 2010, 30(6): 547-557.
[7] K. Chattopadhyay, U. A. Ramagopal, M. Brenowitz, et al. Evo- lution of GITRL immune function: Murine GITRL exhibits uni- que structural and biochemical properties within the TNF super- family. Proceedings of the National Academy of Sciences of USA, 2008, 105(2): 635-640.
[8] T. Placke, H. G. Kopp, H. R. Salih, et al. Glucocorticoid-induced TNFR-related (GITR) protein and its ligand in antitumor immu- nity: Functional role and therapeutic modulation. Clinical and Developmental Immunology, 2010, Article ID: 239083.
[9] D. A. Schaer, J. T. Murphy, J. D. Wolchok, et al. Modulation of GITR for cancer immunotherapy. Current Opinion in Immunol- ogy, 2012, 24(2): 217-224.
[10] A. Alunno, G. Nocentini, O. Bistoni, et al. Expansion of CD4+ CD25−GITR+ regulatory T-cell subset in the peripheral blood of patients with primary Sjögren’s syndrome: Correlation with dis- ease activity. Reumatismo, 2012, 64(5): 293-298.
[11] S. H. Kim, J. Youn. Rheumatoid Fibroblast-like synoviocytes downregulate foxp3 expression by regulatory T cells via GITRL/ GITR interaction. Immune Network, 2012, 12(5): 217-212.
[12] T. P. Lahey, S. D. Loisel, W. Wieland-Alter, et al. Glucocorti- coid-induced tumornecrosis factor receptor family-related protein triggering enhances HIV-specific CD4+ T cell cytokine secretion and protects HIV-specific CD4+ T cells from apoptosis. Journal of Infectious Diseases, 2007, 196(1): 43-49.
[13] B. Wilde, S. Dolff, X. Cai, et al. CD4+CD25+ T-cell populations expressing CD134 and GITR are associated with disease activity inpatients with Wegener’s granulomatosis. Nephrology Dialysis Transplantation, 2009, 24(1): 161-171.
[14] J.-H. Lee, L.-C. Wang, Y.-T. Lin, et al. Inverse correlation be- tween CD4+ regulatory T-cell population and autoantibody lev- els in paediatric patients with systemic lupus erythematosus. Im- munology, 2006, 117(2): 280-286.
[15] W. Łuczynski, N. Wawrusiewicz-Kurylonek, A. Stasiak-Barmuta, et al. Diminished expression of ICOS, GITR and CTLA-4 at the mRNA level in T regulatory cells of children with newly diagnosed type 1 diabetes. Acta Biochimica Polonica, 2009, 56(2): 361-370.
[16] B. Nardelli, L. Zaritskaya, W. McAulife, et al. Osteostat tumor necrosis factor superfamily 18 inhibits osteoclastogenesis and is selectively expressed by vascular endothelial cells. Endocrinol- ogy, 2006, 147(1): 70-78.
[17] L. M. Borrego, M. J. Arroz, P. Videira, et al. Regulatory cells, cytokine pattern and clinical risk factors for asthma in infants and young children with recurrent wheeze. Clinical & Experi- mental Allergy, 2009, 39(8): 1160-1169.
[18] J. Piao, Y. Kamimura, H. Iwai, et al Enhancement of T-cell- mediated antitumour immunity via the ectopically expressed glucocorticoid-induced tumour necrosis factor receptor-related receptor ligand (GITRL) on tumours. Immunology, 2009, 127(4): 489-99.
[19] M. Pietruczuk, M. Eusebio, L. Kraszula, et al. Phenotypic char- acterization of ex vivo CD4+CD25 high CD127 low immune regulatory T cells in allergic asthma: Pathogenesis relevance of their FoxP3, GITR, CTLA-4 and FAS expressions. Journal of Biological Regulators & Homeostatic Agents, 2012, 26(4): 627- 639.
[20] H. Jori, H. Taniguchi, M. Wang, et al. GITR ligand-mediated lo- cal expansion of regulatory T cells and immune privilege of cor- neal allografts. Investigative Ophthalmology & Visual Science, 2010, 51(12): 6556-6565.
[21] A. M. Byrne, E. Goleva, D. Y. Leung, et al. Identification of glucocorticoid-induced TNF receptor-related protein ligand on keratinocytes: Ligation by GITR induces keratinocyte chemo- kine production and augments T-cell proliferation. Journal of In- vestigative Dermatology, 2009, 129(12): 2784-2794.
[22] D. C. Borges, N. M. Araujo, C. R. Cardoso, et al. Different para- site inocula determine the modulation of the immune response and outcome of experimental Trypanosoma cruzi infection. Im- munology, 2013, 138(2): 145-156.
[23] 郑雪平, 胡学强. GITR/GITRL系统在免疫调节中的作用[J]. 细胞与分子免疫学杂志, 2007, 23(4): 385-387.
[24] A. Qin, Z. Wen, Y. Zhou, et al. MicroRNA-126 regulates the induction and function of CD4(+) Foxp3(+) regulatory T cells through PI3K/AKT pathway. Journal of Cellular and Molecular Medicine, 2013, 17(2): 252-264.
[25] 鞠云飞, 孙立锋, 胡华等. CD4+CD25+Treg细胞与支气管哮喘[J]. 中华哮喘杂志(电子版), 2011, 5(6): 439-441.
[26] L. McKelvey, H. Gutierrez, G. Nocentini, et al. The intracellular portion of GITR enhances NGF-promoted neurite growth through an inverse modulation of Erk and NF-κB signalling. Biology Open, 2012, 1(10): 1016-1023.
[27] S. Cuzzocrea, G. Nocentini, R. Di Paola, et al. Proinflammatory role of glucocorticoid-induced TNF receptor-related gene in acute lung inflammation. Immunology, 2006, 177(1): 631-641.
[28] S. P. Mahesh, Z. Li, B. Liu, et al. Expression of GITR ligand abrogates immunosuppressive function of ocular tissue and dif- ferentially modulates inflammatory cytokines and chemokines. European Journal of Immunology, 2006, 36(8): 2128-2138.
[29] G. Nocentini, S. Cuzzocrea, R. Bianchini, et al. Modulation of acute and chronic inflammation of the lung by GITR and its lig- and. Annals of the New York Academy of Sciences, 2007, 1107: 380-391.
[30] A. Joetham, H. Ohnishi, M. Okamoto, et al. Loss of T regulatory cell suppression following signaling through glucocorticoid-in- duced tumor necrosis receptor(GITR) is dependent on c-Jun N- terminal kinase activation. Biological Chemistry, 2012, 287(21): 17100-17108.
[31] L. Kraszula, M. Eusebio, M. Kupczyk, et al. The use of multi- color flow cytometry for identification of functional markers of nTregs in patients with severe asthma. Pneumonologia i Alergologia Polska, 2012, 80(5): 389-401.
[32] S. P. Mahesh, Z. Li, B. Liu, et al. Expression of GITR ligand abrogates immunosuppressive function of ocular tissue and dif- ferentially modulates inlammatory cytokines and chemokines. European Journal of Immunology, 2006, 36(8): 2128-2138.
[33] R. Bianchini, O. Bistoni, A. Alunno, et al. CD4(+) CD25(low) GITR(+) cells: A novel human CD4(+) T-cell population with regulatory activity. European Journal of Immunology, 2011, 41 (8): 2269-2278.
[34] L. Kraszula, M. Eusebio, M. Kupczyk, et al. The use of multi- color flow cytometry for identification of functional markers of nTregs in patients with severe asthma. Pneumonologia i Aler- gologia Polska, 2012, 80(5): 389-401.
[35] F. Kanamaru, P. Youngnak, M. Hashiguchi, et al. Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T-cells. Immunology, 2004, 172(12): 7306-7314.
[36] L. McKelvey, H. Gutierrez, G. Nocentini, et al. The intracellular portion of GITR enhances NGF-promoted neurite growth through an inverse modulation of Erk and NF-κB signalling. Biology Open, 2012, 1(10): 1016-1023.
[37] R. Tomizawa, M. Watanabe, N. Inoue, et al. Association of func- tional GITR gene polymorphisms related to expression of glu- cocorticoid-induced tumour necrosis fac-tor-receptor (GITR) mo- lecules with prognosis of autoimmune thyroid disease. Clinical & Experimental Immunology, 2011, 165(2): 141-147.
[38] J. Kim, W. S. Choi, H. Kang, et al. Conversion of alloanti- gen-speciic CD8+ T-cell anergy to CD8+ T-cell priming through in vivo ligation of glucocorticoid-induced TNF receptor. The Journal of Immunology, 2006, 176(9): 5223-5231.
[39] S. P. Mahesh, Z. Li, B. Liu, et al. Expression of GITR ligand abrogates immunosuppressive function of ocular tissue and diferentially modulates inlammatory cytokines and chemokines. European Journal of Immunology, 2006, 36(8): 2128-2138.
[40] S. Z. Josefowicz, L. F. Lu, et al. Regulatory T cell s: Mecha- nisms of differentiate on and function. Annual Review of Im- munology, 2012, 30(5): 531-564 .
[41] Y. Carrier, M. J. Whitters, J. S. Miyashiro, et al. Enhanced GITR/GITRL interaction augment IL-27 expression and induce IL-10-producing Tr-1 like cells. European Journal of Immunol- ogy, 2012, 42(6): 1393-1404.
[42] A. C. Motta, J. L. Vissers, R. Gras, et al. GITR signaling poten- tiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma. Respiratory Research, 2009, 10(93): 1-8.
[43] M. Patel, D. Xu, P. Kewin, et al. Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collangen-induced arthritis. European Journal of Im- munology, 2005, 35(12): 3581-3590.
[44] S. Cuzzocrea, R. Nocentini, R. Di Paola, et al. Glucocorticoid- induced TNF receptor family gene (GITR) knockout mice exhi- bit a resistance to splanch-nic artery occlusion (SAO) shock. Leukocyte Biology, 2004, 76(5): 933-940.
[45] T. Placke, H. R. Salih and H. G. Kopp. GITR ligand provided by thrombopoietic cells inhibits NK cell antitumor activity. Immu- nology, 2012, 189(1): 154-160.
[46] M. Azuma. Role of Glucocorticoid-induced TNF receptor family gene (GITR)-GITR ligand pathway in innate and adaptive im- munity. Critical Reviews in Immunology, 2010, 30(6): 547-557.
[47] S. Cuzzocrea, R. Nocentini, R. Di Paola, et al. Proinflammatory role of glucocorticoid-induced TNF receptor-related gene in acute lung inflammation. Immunology, 2006, 177(1): 631-641.
[48] T. Placke, H. Sali, H. G. Kopp, et al. GITR liand provided by thrombopoietic cells inhibits NK cell antitumoractivity. The Journal of Immunology, 2012, 189(2): 154-160 .
[49] J. Wang, E. Guan, G. Roderiquez, et al. Synergistic induction of apoptosis in primary CD4+ T cells bymacrophage-tropicHIV-1 and TGF-beta1. The Journal of Immunology, 2001, 167(6): 3360-3366.
[50] D. A. Schaer, J. T. Murphy, J. D. Wolchok, et al. Modulation of GITR for cancer immunotherapy. Current Opinion in Immunol- ogy, 2012, 24(2): 217-224.
[51] L. M. Snell, G. H. Lin, A. J. Mcpherson, et al. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer im- munotherapy. Immunological Reviews, 2011, 244(1): 197-217.
[52] F. Avogadri, J. Yuan, A. Yang, et al. Modulation of CTLA-4 and GITR for cancer immunotherapy. Current Topics in Micro-Bi- ology and Immunology, 2011, 344(10): 211-244.
[53] D. A. Schaer, A. D. Cohen, J. D. Wolchok, et al. Anti-GITR anti- body—Potential clinical applications for tumor immunotherapy. Current Opinion in Investigational Drugs, 2010, 11(12): 1378- 1386.
[54] L. T. Krausz, R. Bianchini, S. Ronchetti, et al. GITR-GITRL system, a novel player in shock and inflammatio. Scientific World Journal, 2007, 1(7): 533-566.
[55] G. Nocentini, S. Ronchetti, S. Cuzzocrea, et al. GIT/GIT RL: More than an efffctor T cell co-stimulatory system. European Journal of Immunology, 2007, 37(5): 1165-1169.
[56] T. Girtsman, Z. Jaffar, M. Ferrini, et al. Natural Foxp3(+) regu- latory T cells inhibit Th2 polarization but are biased toward sup- pression of Th17-driven lung inflammation. Leukocyte Biology, 2010, 88(3): 537-546.