Type I Interferon-induced neuronal damage: a study of the cellular and molecular mechanisms mediating interferon neurotoxicity

Type I interferons (IFNs) are known to cause neuropsychiatric side effects, including cognitive and mood disturbances, through mechanisms still not completely defined. To gain more information about type I IFN neurotoxicity, I investigated whether these cytokines could act directly on neuronal cells and regulate intracellular signaling pathways involved in cell death. In primary cultures of mouse cortical neurons acute exposure to IFN-β induces a marked tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 1 and 3, whereas long-term exposure to the cytokine increased the number of neuronal cells displaying an increased labeling for cleaved caspase 3. In human SH-SY5Y neuroblastoma cells, used as a neuronal cell model, type I IFNs rapidly stimulated the tyrosine phosphorylation of Janus kinase (JAK) and STAT1, STAT3 and STAT5 and this response was antagonized by blockade of type I IFN receptor. Prolonged exposure to IFN-β induced apoptotic cell death accompanied by cytochrome C release, cleavage of caspase-9, -7, -3 and poly-(ADP ribose) polymerase (PARP), DNA fragmentation and p38 mitogenactivated protein kinase (p38 MAPK) phosphorylation. JAK inhibition reduced IFN-β- stimulated Tyk2 and STAT1 phosphorylation, STAT1 transcriptional activity, induction of double-stranded RNA-activated protein kinase (PKR), caspase cleavage and p38 MAPK phosphorylation. PKR induction was associated with enhanced PKR activity and chemical inhibition of PKR reduced IFN-stimulated caspase activation. Moreover, long-term IFN-β treatment led to down-regulation of phosphatidylinositol 3- kinase (PI3K)/protein kinase B (Akt) signaling and IFN-β-induced apoptosis was attenuated in cells expressing constitutively active Akt. The proapoptotic effect of IFNs was markedly attenuated by pharmacological blockade of either glycogen 8 synthase kinase-3 (GSK-3) or p38 MAPK. In retinoic acid-differentiated SH-SY5Y cells, treatment with IFN-β inhibited BDNF-induced regulation of Akt and GSK-3β, activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), phosphorylation of tyrosine hydroxylase, and neuritogenesis. Thus, type I IFNs can directly impair neuronal survival by regulating multiple mechanisms, including activation of the canonical JAK-STAT signaling and the ancillary p38 MAPK pathway and down-regulation of the PI3K/Akt and ERK1/2 signaling systems. The final outcome of these molecular events is the activation of the apoptotic program and impaired neuronal differentiation in response to neurotrophic stimuli. It is proposed that these actions directed on neuronal cells may contribute to the neuropsychiatric disturbances elicited by these cytokines.