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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 IFN-mediated induction of selective ISGs in HCV patients with IFN-induced depression (in vivo) and psychiatric patients with a severe depressive episode (SDE, in vitro).Total RNA was isolated from peripheral blood of hepatitis C virus (HCV) infected patients with (n = 11, “HCV-D”) or without (n = 11, “HCV-N”) IFN-induced depression 12 hours before and 12 hours after the first injection of pegylated IFN-α2a. Expression of IFN stimulated genes (ISGs) was analyzed by quantitative RT-PCR (panel A: GCH1, TOR1B; panel B: DYNLT1, DISC1; panel C: MX1, ISG15). To validate the data in an independent cohort, PBMC were isolated from 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”) and stimulated with 100 U/mL pegylated IFN-α2a in vitro for 16 h followed by isolation of total RNA. Data are shown as box plots (range, 25% and 75% percentile, mean).
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pone-0038668-g001: Enhanced IFN-mediated induction of selective ISGs in HCV patients with IFN-induced depression (in vivo) and psychiatric patients with a severe depressive episode (SDE, in vitro).Total RNA was isolated from peripheral blood of hepatitis C virus (HCV) infected patients with (n = 11, “HCV-D”) or without (n = 11, “HCV-N”) IFN-induced depression 12 hours before and 12 hours after the first injection of pegylated IFN-α2a. Expression of IFN stimulated genes (ISGs) was analyzed by quantitative RT-PCR (panel A: GCH1, TOR1B; panel B: DYNLT1, DISC1; panel C: MX1, ISG15). To validate the data in an independent cohort, PBMC were isolated from 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”) and stimulated with 100 U/mL pegylated IFN-α2a in vitro for 16 h followed by isolation of total RNA. Data are shown as box plots (range, 25% and 75% percentile, mean).

Mentions: To validate these candidate genes in different patient populations under different experimental conditions, the in vitro response to pegylated IFN-α2a was studied in a cohort of 22 psychiatric patients that were hospitalized for a SDE. Compared to healthy controls, pegylated IFN-α2a led to a significantly higher induction of GCH1, TOR1B (Figure 1A), DYNLT1 and DISC1 (Figure 1B) while there was a trend towards higher induction for MEF2A and ST3GAL5 (data not shown). No difference was observed for classical ISGs like MX1 or ISG15 (Figure 1C) as well as IFIT1 and IFI16 (data not shown) suggesting that there is a selective rather than a general hyper-responsiveness to type I IFNs in these patients.


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 IFN-mediated induction of selective ISGs in HCV patients with IFN-induced depression (in vivo) and psychiatric patients with a severe depressive episode (SDE, in vitro).Total RNA was isolated from peripheral blood of hepatitis C virus (HCV) infected patients with (n = 11, “HCV-D”) or without (n = 11, “HCV-N”) IFN-induced depression 12 hours before and 12 hours after the first injection of pegylated IFN-α2a. Expression of IFN stimulated genes (ISGs) was analyzed by quantitative RT-PCR (panel A: GCH1, TOR1B; panel B: DYNLT1, DISC1; panel C: MX1, ISG15). To validate the data in an independent cohort, PBMC were isolated from 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”) and stimulated with 100 U/mL pegylated IFN-α2a in vitro for 16 h followed by isolation of total RNA. Data are shown as box plots (range, 25% and 75% percentile, mean).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368901&req=5

pone-0038668-g001: Enhanced IFN-mediated induction of selective ISGs in HCV patients with IFN-induced depression (in vivo) and psychiatric patients with a severe depressive episode (SDE, in vitro).Total RNA was isolated from peripheral blood of hepatitis C virus (HCV) infected patients with (n = 11, “HCV-D”) or without (n = 11, “HCV-N”) IFN-induced depression 12 hours before and 12 hours after the first injection of pegylated IFN-α2a. Expression of IFN stimulated genes (ISGs) was analyzed by quantitative RT-PCR (panel A: GCH1, TOR1B; panel B: DYNLT1, DISC1; panel C: MX1, ISG15). To validate the data in an independent cohort, PBMC were isolated from 11 healthy controls (“co-N”) and 22 patients hospitalized for a SDE (“co-D”) and stimulated with 100 U/mL pegylated IFN-α2a in vitro for 16 h followed by isolation of total RNA. Data are shown as box plots (range, 25% and 75% percentile, mean).
Mentions: To validate these candidate genes in different patient populations under different experimental conditions, the in vitro response to pegylated IFN-α2a was studied in a cohort of 22 psychiatric patients that were hospitalized for a SDE. Compared to healthy controls, pegylated IFN-α2a led to a significantly higher induction of GCH1, TOR1B (Figure 1A), DYNLT1 and DISC1 (Figure 1B) while there was a trend towards higher induction for MEF2A and ST3GAL5 (data not shown). No difference was observed for classical ISGs like MX1 or ISG15 (Figure 1C) as well as IFIT1 and IFI16 (data not shown) suggesting that there is a selective rather than a general hyper-responsiveness to type I IFNs in these patients.

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