Interferon-alpha treatment differenzially modifies the expression of depression-related interferon-inducible genes in vivo and in vitro

Aims: Consensus-interferon-alpha (cIFN), used in the current therapy for hepatitis C, is associated with an elevated risk of depression. Our previous gene expression analysis of peripheral blood of de novo depressed-HCV patients and brain of suicidal individuals showed 16 genes strongly upregulated, which may be related to development of neuropsychiatric disorders.

Aim: The aim of this study is to elucidate the effect of cIFN on the depression-related interferon-inducible genes (DRIIs) expression in hippocampus, a brain area which is closely related to depression development, by the use of in vitro and in vivo mouse models.

Methods: Cells of the murine hippocampal-neuronal cell line HT22, were cultured at 7,5×10⁴cells/well in DMEM including 10% FCS. After 20 hours of culture they were stimulated with 10.000 IU of cIFN and collected after 24 hours. Additionally, C57BL/6 mice underwent treatment with 500.000 IU of cIFN through tail vein injection. After 24 hours hippocampus was isolated. The expression of the interferon-stimulated gene 15 (ISG15) and 9 of the DRIIs was determined by RT-PCR.

Results: The in vitro and in vivo stimulation with cIFN showed a significantly strong induction of ISG15 gene expression (p<0.0001). Concerning to DRIIs, differenzial expression responses were observed, showing a strong and differenzial upregulation of Stat1, Grlx and Rtp4 in both systems, whereas Rbck was upregulated in vivo and Ube2L6 only in vitro. The rest of the DRIIs did not vary their expression levels (data not shown).

Conclusion: The cIFN-mediated ISG15 induction is consistent in both systems, indicating that the treatment promotes a clear answer of the interferon-related pathways The induction of several DRIIs by cIFN in the HT22 murine hippocampal cell line as well as in the murine hippocampus defers, suggesting than in vivo additional factors may participate in the answer to the treatment promoting the upregulation of Rbck. Our previous results are partially validated in this study, as some of the predefined DRIIs responded to cIFN treatment. The strong activation of DRIIs is highly interesting for a better understanding of the pathway of the neuropsychiatric side effects that HCV patients may experience during the interferon-alpha therapy.