摘要
背景：TNF超家族中的细胞因子在神经变性过程中起着重要的作用。肿瘤坏死因子相关凋亡诱导配体（TRAIL），在神经损伤的时候释放，现已被证明有效的调解和维持神经过程导致神经元死亡。与TRAIL一样，糖皮质激素诱导的肿瘤坏死因子受体的细胞因子配体（GITRL）能够介导凋亡信号传导。报道表明TRAIL和其他细胞因子之间的关系，尽管缺乏大量数据，但到目前为止，仍然可以找到与GITRL/TRAIL相关的内容。 方法：在这里，我们用hcn-2人类皮层神经细胞系研究了人类神经退行性疾病的体外模型TRAIL 和 GITRL系统之间可能的相互作用。培养hcn-2神经元，用GITRL或是 TRAIL在不同的时间孵育，然后通过核酸和蛋白表达的测定。实时荧光定量PCR分析表明，人类大脑皮质神经元细胞系hcn-2不表达GITRL mRNA，但后者与TRAIL诱导治疗后能表达。mRNA蛋白的Western blot实验分析证实，无论是控制组培养，还是TRAIL治疗后，hcn-2细胞都不表达GITRL受体的mRNA，细胞活力检测结果显示，当涉及到GITRL，反证实验提示如果阻断GITRL进行，TRAIL介导的毒性明显降低。结果表明，在神经变性过程GITRL/TRAIL过多意味着细胞因子对神经元中造成不良的影响增强，最终导致更多的细胞损伤和死亡。
关键词: 诱导细胞凋亡的神经退行性疾病，炎症，肿瘤坏死因子超家族，抗菌药物可调节，治疗靶点，HCN - 2细胞系。
[2]
Griffin WS. Neuroinflammatory cytokine signaling and Alzheimer’s disease. N Engl J Med 368(8): 770-1. (2013).
[3]
Almasan A, Ashkenazi A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev 14(3-4): 337-48. (2003).
[4]
Cantarella G, Uberti D, Carsana T, Lombardo G, Bernardini R, Memo M. Neutralization of TRAIL death pathway protects human neuronal cell line from beta-amyloid toxicity. Cell Death Differ 10(1): 134-41. (2003).
[5]
Cantarella G, Bucolo C, Di Benedetto G, Pezzino S, Lempereur L, Calvagna R, et al. Protective effects of the sigma agonist Pre-084 in the rat retina. Br J Ophthalmol 91: 1382-4. (2007).
[6]
Ronsisvalle N, Di Benedetto G, Parenti C, Amoroso S, Bernardini R, Cantarella G. CHF5074 protects SH-SY5Y human neuronal-like cells from amyloidbeta 25-35 and tumor necrosis factor related apoptosis inducing ligand toxicity in vitro. Curr Alzheimer Res 11(7): 714-24. (2014).
[7]
Cantarella G, Di Benedetto G, Puzzo D, Privitera L, Loreto C, Saccone S, et al. Neutralization of TNFSF10 ameliorates functional outcome in a murine model of Alzheimer’s disease. Brain J Neurol 138(Pt 1): 203-16. (2015).
[8]
Nocentini G, Cuzzocrea S, Genovese T, Bianchini R, Mazzon E, Ronchetti S, et al. Glucocorticoid-induced tumor necrosis factor receptor-related (GITR)-Fc fusion protein inhibits GITR triggering and protects from the inflammatory response after spinal cord injury. Mol Pharmacol 73(6): 1610-21. (2008).
[9]
Cantarella G, Di Benedetto G, Scollo M, Paterniti I, Cuzzocrea S, Bosco P, et al. Neutralization of tumor necrosis factor-related apoptosis-inducing ligand reduces spinal cord injury damage in mice. Neuropsychopharmacol 35(6): 1302-14. (2010).
[10]
Nocentini G, Giunchi L, Ronchetti S, Krausz LT, Bartoli A, Moraca R, et al. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc Natl Acad Sci USA 94(12): 6216-21. (1997).
[11]
Kwon B, Yu KY, Ni J, Yu GL, Jang IK, Kim YJ, et al. Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand. J Biol Chem 274(10): 6056-61. (1999).
[12]
Spinicelli S, Nocentini G, Ronchetti S, Krausz LT, Bianchini R, Riccardi C. GITR interacts with the pro-apoptotic protein Siva and induces apoptosis. Cell Death Differ 9(12): 1382-4. (2002).
[13]
Chen X, Du Y, Lin X, Qian Y, Zhou T, Huang Z. CD4+CD25+ regulatory T cells in tumor immunity. Int Immunopharmacol 34: 244-9. (2016).
[14]
Kroemer G, Moreno de Alboran I, Gonzalo JA, Martinez C. Immunoregulation by cytokines. Crit Rev Immunol 13(2): 163-91. (1993).
[15]
Cantarella G, Pignataro G, Di Benedetto G, Anzilotti S, Vinciguerra A, Cuomo O, et al. Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype. Cell Death Dis 5: e1331. (2014).
[16]
Poulton LD, Nolan KF, Anastasaki C, Waldmann H, Patton EE. A novel role for Glucocorticoid-Induced TNF Receptor Ligand (Gitrl) in early embryonic zebrafish development. Int J Dev Biol 54(5): 815-25. (2010).
[17]
Nocentini G, Riccardi C. GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur J Immunol 35(4): 1016-22. (2005).
[18]
Nocentini G, Riccardi C. GITR: a modulator of immune response and inflammation. Adv Exp Med Biol 647: 156-73. (2009).
[19]
Shevach EM, Stephens GL. The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity? Nat Rev Immunol 6(8): 613-8. (2006).
[20]
Nocentini G, Ronchetti S, Cuzzocrea S, Riccardi C. GITR/GITRL: more than an effector T cell co-stimulatory system. Eur J Immunol 37(5): 1165-9. (2007).
[21]
Aktas O, Smorodchenko A, Brocke S, Infante-Duarte C, Schulze Topphoff U, Vogt J, et al. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46(3): 421-32. (2005).
[22]
Hwang H, Lee S, Lee WH, Lee HJ, Suk K. Stimulation of glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) induces inflammatory activation of microglia in culture. J Neurosci Res 88(10): 2188-96. (2010).
[23]
Kim BJ, Li Z, Fariss RN, Shen DF, Mahesh SP, Egwuagu C, et al. Constitutive and cytokine-induced GITR ligand expression on human retinal pigment epithelium and photoreceptors. Invest Ophthalmol Vis Sci 45(9): 3170-6. (2004).
[24]
Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J, et al. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J Neurosci J Soc Neurosci 19(10): 3809-17. (1999).
[25]
Cantarella G, Lempereur L, D’Alcamo MA, Risuglia N, Cardile V, Pennisi G, et al. Trail interacts redundantly with nitric oxide in rat astrocytes: potential contribution to neurodegenerative processes. J Neuroimmunol 182(1-2): 41-7. (2007).
[27]
Ferraro E, Corvaro M, Cecconi F. Physiological and pathological roles of Apaf1 and the apoptosome. J Cell Mol Med 7(1): 21-34. (2003).
[28]
Kim JD, Choi BK, Bae JS, Lee UH, Han IS, Lee HW, et al. Cloning and characterization of GITR ligand. Genes Immun 4(8): 564-9. (2003).
[29]
Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation - tipping the balance in atherosclerosis? Thromb Haemost 106(5): 804-13. (2011).
[30]
Paludan SR. Synergistic action of pro-inflammatory agents: cellular and molecular aspects. J Leukoc Biol 67(1): 18-25. (2000).
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