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.