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Interferon (IFN)-alpha upregulates serotonin (5-HT) uptake and serotonin transporter (5-HTT) messenger ribonucleic acid (mRNA) expression in immune cells, which implies the mechanism underlying IFN-alpha-induced depression. However, the signal transduction of this effect remains unclear. We investigated whether the effects of IFN-alpha on the functions of 5-HTT were related to mitogen-activated protein kinase (MAPK). By performing Western blotting, real-time reverse transcriptase-polymerase chain reaction and [3H]5-HT labelling, we examined MAPK phosphorylation, 5-HTT mRNA expression and 5-HT uptake in Jurkat T cells. The cells had been cultured for different time periods (1) with IFN-alpha alone and (2) preincubated with either MAPK inhibitors or with the selective serotonin reuptake inhibitor, fluoxetine, and subsequently cultured along with IFN-alpha. The levels of MAPK phosphorylation, 5-HTT mRNA expression and 5-HT uptake all increased in the IFN-alpha-treated cells but were blocked in those that were pretreated with MAPK inhibitors and fluoxetine. These results appear to clarify the association of depression with IFN-alpha-induced 5-HT uptake that reduces the 5-HT levels and IFN-alpha-regulated transcription of 5-HTT; further, the results suggest the involvement of MAPK in this process.

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Clinical reports document that depression as a side effect is more prevalent in hepatic patients given interferon (IFN)-a therapy than in those given lamivudine. The mechanisms, however, are poorly understood. Serotonin transporter (5-HTT), via uptake of serotonin (5-HT) into presynaptic serotoninergic neurons, is an initial action site for antidepressants. Real-time polymerase chain reaction (PCR) was used to quantify 5-HTT mRNA expression in immune cells in order to evaluate whether 5-HTT acted as an indicator of depression. Results showed that the 5-HTT mRNA expression was much higher in T-cell and B-cell lines than that in a monocytic cell line. Treatment with either lamivudine or ribavirin reduced the 5-HTT mRNA expression, protein level and 5-HT uptake in T-cell line. Treatment with IFN-a, however, increased those levels in the same group. A similar effect was observed in peripheral blood mononuclear cells (PBMC). Mimicking clinical use by treating PBMC with a combination of IFN-a and ribavirin increased the 5-HTT mRNA expression level. Our study indicates that these therapeutic drugs regulate 5-HTT expression, which implies that 5-HTT might be a trait marker in IFN-a-induced depression after hepatic therapy.