The Proinflammatory Cytokine GITRL Contributes to TRAIL-mediated Neurotoxicity in the HCN-2 Human Neuronal Cell Line.
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.
['Di Benedetto|Giulia|G|', 'Saccone|Salvatore|S|', 'Lempereur|Laurence|L|', 'Ronsisvalle|Nicole|N|', 'Nocentini|Giuseppe|G|', 'Bianchini|Rodolfo|R|', 'Riccardi|Carlo|C|', 'Bernardini|Renato|R|', 'Cantarella|Giuseppina|G|']
D017209:Apoptosis D020169:Caspases D002460:Cell Line D002470:Cell Survival D002540:Cerebral Cortex D015870:Gene Expression D053450:Glucocorticoid-Induced TNFR-Related Protein D006801:Humans D015213:Neuroimmunomodulation D009474:Neurons D010766:Phosphorylation D012333:RNA, Messenger D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand D050796:STAT3 Transcription Factor D053221:TNF-Related Apoptosis-Inducing Ligand D000079424:Tumor Necrosis Factor Inhibitors D048069:Tumor Necrosis Factors
TNF superfamily Neurodegeneration HCN-2 cell
line neuroinflammation proapoptotic cytokines therapeutic targets