Type I interferons (IFNs) are known to cause neuropsychiatric side effects, including cognitive, emotional and mood disturbances, through mechanisms still not completely defined. We have previously reported that human SH-SY5Y neuroblastoma cells express functional type I IFN receptors and are highly responsive to the cellular actions of these cytokines. In the present study we use this neuronal cell model to investigate the effects of IFN-β on p38-mitogen activated protein kinase (p38-MAPK), which has been reported to mediate stress-induced dysphoria, and on intracellular signaling pathways regulated by brain-derived neurotrophic factor (BDNF), which exerts antidepressant activity. We found that cell treatment with IFN-β induced p38-MAPK activation which was prevented by Janus kinase inhibition. Blockade of p38-MAPK with the inhibitor SB203580 prevented IFN-β-induced caspase-7 activation and poly-(ADP ribose) polymerase cleavage. In retinoic-acid differentiated SH-SY5Y cells, treatment with IFN-β inhibited BDNF-induced activation of the protein kinase Akt and phosphorylation of glycogen synthase kinase-3β, a key enzyme in the development of mood disorders. These data indicate that in neuronal cells IFN-β can up-regulate molecular pathways mediating stress-induced cell damage and down-regulate BDNF signaling governing neuronal survival, mood and cognition.
Interferon-β activates neuronal signaling pathways associated with stress and depression
DEDONI, SIMONA;OLIANAS, MARIA CONCETTA;ONALI, PIER LUIGI
2010-01-01
Abstract
Type I interferons (IFNs) are known to cause neuropsychiatric side effects, including cognitive, emotional and mood disturbances, through mechanisms still not completely defined. We have previously reported that human SH-SY5Y neuroblastoma cells express functional type I IFN receptors and are highly responsive to the cellular actions of these cytokines. In the present study we use this neuronal cell model to investigate the effects of IFN-β on p38-mitogen activated protein kinase (p38-MAPK), which has been reported to mediate stress-induced dysphoria, and on intracellular signaling pathways regulated by brain-derived neurotrophic factor (BDNF), which exerts antidepressant activity. We found that cell treatment with IFN-β induced p38-MAPK activation which was prevented by Janus kinase inhibition. Blockade of p38-MAPK with the inhibitor SB203580 prevented IFN-β-induced caspase-7 activation and poly-(ADP ribose) polymerase cleavage. In retinoic-acid differentiated SH-SY5Y cells, treatment with IFN-β inhibited BDNF-induced activation of the protein kinase Akt and phosphorylation of glycogen synthase kinase-3β, a key enzyme in the development of mood disorders. These data indicate that in neuronal cells IFN-β can up-regulate molecular pathways mediating stress-induced cell damage and down-regulate BDNF signaling governing neuronal survival, mood and cognition.
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