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Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy.

Schlaak JF, Trippler M, Hoyo-Becerra C, Erim Y, Kis B, Wang B, Scherbaum N, Gerken G - PLoS ONE (2012)

Bottom Line: In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients.Our data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms.These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany. joerg.schlaak@uni-due.de

ABSTRACT

Background: Though an important percentage of patients with chronic hepatitis C virus (HCV) undergoing interferon (IFN) therapy develop depressive symptoms, the role of the IFN system in the pathogenesis of depressive disorders is not well understood.

Methods: 50 patients with HCV infection were treated with standard combination therapy (pegylated IFN-α2a/ribavirin). IFN-induced gene expression was analyzed to identify genes which are differentially regulated in patients with or without IFN-induced depression. For validation, PBMC from 22 psychiatric patients with a severe depressive episode (SDE) and 11 controls were cultivated in vitro with pegylated IFN-α2a and gene expression was analyzed.

Results: IFN-induced depression in HCV patients was associated with selective upregulation of 15 genes, including 6 genes that were previously described to be relevant for major depressive disorders or neuronal development. In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients.

Conclusions: Our data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms. These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders.

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Related in: MedlinePlus

Enhanced ISG expression and IFN-production in psychiatric patients with a severe depressive episode (SDE).Panel A. After 24 h of in vitro incubation without any further stimuli, total RNA was isolated from peripheral blood mononuclear cells of 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”). Panel B. Total RNA was isolated directly from unseparated peripheral blood of healthy controls (“co-N”, n = 11), SDE patients (“co-D, n = 22”) and HCV patients without (“HCV-N”, n = 11) or with (“HCV-D”, n = 11) IFN-induced depression. Expression of IFN stimulated genes (ISGs) and IFN-β was analyzed by quantitative RT-PCR. Data (copies per 100,000 copies of ACTB) are shown as box plots (range, 25% and 75% percentile, mean).
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pone-0038668-g002: Enhanced ISG expression and IFN-production in psychiatric patients with a severe depressive episode (SDE).Panel A. After 24 h of in vitro incubation without any further stimuli, total RNA was isolated from peripheral blood mononuclear cells of 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”). Panel B. Total RNA was isolated directly from unseparated peripheral blood of healthy controls (“co-N”, n = 11), SDE patients (“co-D, n = 22”) and HCV patients without (“HCV-N”, n = 11) or with (“HCV-D”, n = 11) IFN-induced depression. Expression of IFN stimulated genes (ISGs) and IFN-β was analyzed by quantitative RT-PCR. Data (copies per 100,000 copies of ACTB) are shown as box plots (range, 25% and 75% percentile, mean).

Mentions: When baseline levels of ISGs were studied in patients with SDE after 24h without additional stimulation, a significant upregulation of classical ISGs (i.e. STAT1, IFIT1) compared to healthy controls was observed (Figure 2A) suggesting that there is an increased production of endogenous IFNs in these patients. To test this hypothesis, we assessed the in vivo baseline levels of the most abundant IFN-α subtypes (IFN-α1 and -α2), IFN-β and IFN-γ by quantitative RT-PCR (Table 4, Figure 2B). The most striking finding was a significant upregulation of IFN-β production in patients with SDE compared to controls. Also, there were increased mRNA levels of IFN-α1 and IFN-α2 and a trend towards higher levels of IFN-γ suggesting a broad activation of type I and II IFN production in SDE patients. Interestingly, IFN-β expression was profoundly enhanced in HCV patients before therapy consistent with a direct stimulation by HCV through the Toll-like receptor (TLR) system (Table 4). IFN-γ mRNA levels were elevated in HCV patients that could be explained by activation of the PBMC-derived immunity while no significant changes in IFN-α mRNA levels were observed.


Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy.

Schlaak JF, Trippler M, Hoyo-Becerra C, Erim Y, Kis B, Wang B, Scherbaum N, Gerken G - PLoS ONE (2012)

Enhanced ISG expression and IFN-production in psychiatric patients with a severe depressive episode (SDE).Panel A. After 24 h of in vitro incubation without any further stimuli, total RNA was isolated from peripheral blood mononuclear cells of 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”). Panel B. Total RNA was isolated directly from unseparated peripheral blood of healthy controls (“co-N”, n = 11), SDE patients (“co-D, n = 22”) and HCV patients without (“HCV-N”, n = 11) or with (“HCV-D”, n = 11) IFN-induced depression. Expression of IFN stimulated genes (ISGs) and IFN-β was analyzed by quantitative RT-PCR. Data (copies per 100,000 copies of ACTB) are shown as box plots (range, 25% and 75% percentile, mean).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368901&req=5

pone-0038668-g002: Enhanced ISG expression and IFN-production in psychiatric patients with a severe depressive episode (SDE).Panel A. After 24 h of in vitro incubation without any further stimuli, total RNA was isolated from peripheral blood mononuclear cells of 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”). Panel B. Total RNA was isolated directly from unseparated peripheral blood of healthy controls (“co-N”, n = 11), SDE patients (“co-D, n = 22”) and HCV patients without (“HCV-N”, n = 11) or with (“HCV-D”, n = 11) IFN-induced depression. Expression of IFN stimulated genes (ISGs) and IFN-β was analyzed by quantitative RT-PCR. Data (copies per 100,000 copies of ACTB) are shown as box plots (range, 25% and 75% percentile, mean).
Mentions: When baseline levels of ISGs were studied in patients with SDE after 24h without additional stimulation, a significant upregulation of classical ISGs (i.e. STAT1, IFIT1) compared to healthy controls was observed (Figure 2A) suggesting that there is an increased production of endogenous IFNs in these patients. To test this hypothesis, we assessed the in vivo baseline levels of the most abundant IFN-α subtypes (IFN-α1 and -α2), IFN-β and IFN-γ by quantitative RT-PCR (Table 4, Figure 2B). The most striking finding was a significant upregulation of IFN-β production in patients with SDE compared to controls. Also, there were increased mRNA levels of IFN-α1 and IFN-α2 and a trend towards higher levels of IFN-γ suggesting a broad activation of type I and II IFN production in SDE patients. Interestingly, IFN-β expression was profoundly enhanced in HCV patients before therapy consistent with a direct stimulation by HCV through the Toll-like receptor (TLR) system (Table 4). IFN-γ mRNA levels were elevated in HCV patients that could be explained by activation of the PBMC-derived immunity while no significant changes in IFN-α mRNA levels were observed.

Bottom Line: In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients.Our data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms.These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany. joerg.schlaak@uni-due.de

ABSTRACT

Background: Though an important percentage of patients with chronic hepatitis C virus (HCV) undergoing interferon (IFN) therapy develop depressive symptoms, the role of the IFN system in the pathogenesis of depressive disorders is not well understood.

Methods: 50 patients with HCV infection were treated with standard combination therapy (pegylated IFN-α2a/ribavirin). IFN-induced gene expression was analyzed to identify genes which are differentially regulated in patients with or without IFN-induced depression. For validation, PBMC from 22 psychiatric patients with a severe depressive episode (SDE) and 11 controls were cultivated in vitro with pegylated IFN-α2a and gene expression was analyzed.

Results: IFN-induced depression in HCV patients was associated with selective upregulation of 15 genes, including 6 genes that were previously described to be relevant for major depressive disorders or neuronal development. In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients.

Conclusions: Our data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms. These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders.

Show MeSH
Related in: MedlinePlus