Abstract
Background: Cytokines belonging to the TNF superfamily play a relevant role in neurodegenerative processes. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), released during neuronal injury, has proven to potently mediate and sustain neurotoxic processes leading to neuronal death. Similarly to TRAIL, the cytokine Glucocorticoid-induced TNF receptor ligand (GITRL) is able to transduce proapoptotic signals. In spite of the array of reports suggesting relationships between TRAIL and other cytokines, scanty data are, so far, available about a GITRL/TRAIL crosstalk.
Methods: Here, we investigated possible interactions between TRAIL and the GITRL system in an in vitro model of neurodegeneration, using the human cortical neuronal cell line HCN-2. Cultured HCN-2 neurons were incubated at different times with GITRL and/or TRAIL, and thereafter nucleic acid and protein expression were measured. Real-time PCR analysis showed that the human cortical neuronal cell line HCN-2 does not express GITRL mRNA, but the latter is induced after treatment with TRAIL. In addition, HCN-2 cells did not express the GITRL receptor GITR mRNA, neither in control cultures, nor after treatment with TRAIL. All mRNA data were confirmed by western blot analysis of proteins. Cell viability assay showed that TRAIL, when associated to GITRL, was able to exert additive toxic effects. A counterproof was provided in experiments performed blocking GITRL, in which TRAIL-mediated toxicity appeared significantly reduced. Results suggest that GITRL/TRAIL redundancy during neurodegenerative processes implies extended potentiation of detrimental effects of both cytokines on neurons, eventually leading to larger cell damage and death. Conclusion: Finally, characterization of novel molecular targets within the TRAIL/GITRL interplay may represent a platform for innovative therapy of neurodegenerative disorders.Keywords: Neurodegeneration, proapoptotic cytokines, TNF superfamily, neuroinflammation, therapeutic targets, HCN-2 cell line.
[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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