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The Proinflammatory Cytokine GITRL Contributes to TRAIL-mediated Neurotoxicity in the HCN-2 Human Neuronal Cell Line

[ Vol. 14 , Issue. 10 ]

Author(s):

Giulia Di Benedetto, Salvatore Saccone, Laurence Lempereur, Nicole Ronsisvalle, Giuseppe Nocentini, Rodolfo Bianchini, Carlo Riccardi, Renato Bernardini and Giuseppina Cantarella*   Pages 1090 - 1101 ( 12 )

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.

Affiliation:

Departments of Biomedical and Biotechnological Sciences, Section of Pharmacology, Animal Biology, University of Catania School of Medicine and School of Biology, Catania, Departments of Biomedical and Biotechnological Sciences, Section of Pharmacology, Departments of Biomedical and Biotechnological Sciences, Section of Pharmacology, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Departments of Biomedical and Biotechnological Sciences, Section of Pharmacology, Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine and School of Biology, Catania



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