Concomitant Interferon Alpha Stimulation and TLR3 Activation Induces Neuronal Expression of Depression-Related Genes That Are Elevated in the Brain of Suicidal Persons

Abstract

We have previously identified 15 genes that are associated with the development of severe depressive side effects during the standard therapy with interferon alpha and ribavirin in the peripheral blood of hepatitis C virus infected patients. An enhanced expression of these genes was also found in the blood of psychiatric patients suffering severe depressive episode. Herein, we demonstrate that the same depression-related interferon-inducible genes (DRIIs) are also upregulated in post-mortem brains of suicidal individuals. Using cultured mouse hippocampal and prefrontal neurons we show that costimulation with murine IFN (mIFN) and the TLR3 agonist poly(I:C) promotes the expression of the described DRIIs, at the same time inducing pro-inflammatory cytokine expression through Stat1 and Stat3 activation, promoting neuronal apoptosis. Consequently, the upregulation of selective DRIIs, production of inflammatory cytokines and inhibition of neuronal plasticity may be involved in the pathogenesis of IFN-associated depression.

The influence of inflammatory cytokines in physiopathology of suicidal behavior

“…Taken together these data, it would seem that the logical connection between the diverse disorders and suicide involves inflammation (inflammatory cytokines), depressed mood and as consequence an enhanced suicide risk (Kalkman, 2011). Another important correlation was supported by epidemiological data that indicate that 59-87% of suicide victims suffer from major depression at the moment of decease (Hoyo-Becerra et al, 2013;Henriksson et al, 1993;Harwood et al, 2001). One third of individuals suffering of major depression shows elevated peripheral inflammation markers, supporting the hypothesis that inflammation may play an important role in the pathophysiology of this entity (Vargas et al, 2013).…”

“…Hoyo-Becerra et al also studied an IFN treatment and Toll like receptor (TLR3) stimulation, together in vitro in murine neurons. This IFN and TRL3 co-stimulation not only up regulates the DRIIs, but also was a strong inducer of pro-inflammatory cytokine expression in neurons through Signal transducer and activator of transcription 1 (Stat1) and Signal transducer and activator of transcription 3 (Stat3) activation (Hoyo-Becerra et al, 2013).…”

“…It was demonstrated that Interferon-α (IFN-α), a pro-inflammatory cytokine used as treatment for a variety of chronic viral infections and malignant disorders, induces depressive symptoms in 30-50% of the patients undergoing a long lasting treatment. The IFN-associated depression may lead even to the development of suicidal ideation and behavior (Hoyo-Becerra et al, 2013;Miller and Lecture, 2009;Raison et al, 2005). In this line, IFN-α has been shown to increase serum concentrations of pro-inflammatory cytokines such as interleukin IL-1, IL-6, tumor necrosis factor-α (TNF-α) and IFN-ϒ (Lafon et al, 2006) which are factors increased in suicidal behavior and also in depressive neuropsychiatric patients (Hoyo-Becerra et al, 2013).…”

“…Notably, IL-6 is not only found to be elevated in the cerebrospinal fluid of suicide attempters (O'Donovan et al, 2012), even its levels in the peripheral blood have been proposed as a biological marker discriminating suicide attempters from depressed patients without suicidal ideation (Monje et al, 2011;O'Donovan et al, 2012;Hoyo-Becerra et al, 2013).…”

Genomewide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide

“…18 STAT1 gene expression is significantly increased in individuals with severe depression, and in postmortem brain tissue of individuals who died by suicide. 19 Of the six cases with phenotype data sharing this region, four had depression, three had anxiety, two had personality disorders, three had evidence of obesity, and two had asthma.…”