Concomitant interferon alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons

Carolina Hoyo-Becerra; Anastasia Huebener; Martin Trippler; Melanie Lutterbeck; Zijian J Liu; Kurt Truebner; Thomas Bajanowski; Guido Gerken; Dirk M Hermann; Joerg F Schlaak

doi:10.1371/journal.pone.0083149

Concomitant interferon alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons

PLoS One. 2013 Dec 31;8(12):e83149. doi: 10.1371/journal.pone.0083149. eCollection 2013.

Affiliations

¹ Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
² Department of Anatomy, Tongji Medical College of Huazhong, University of Science and Technology, Wuhan City, P.R.China.
³ Institute for Forensic Medicine, University Hospital of Essen, Essen, Germany.
⁴ Department of Neurology, University Hospital of Essen, Essen, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Apoptosis / drug effects
Brain / drug effects*
Brain / metabolism*
Cells, Cultured
Child
Cytokines / biosynthesis
Depression / etiology*
Depression / genetics*
Depression / metabolism
Female
Hepatitis C, Chronic / complications
Hepatitis C, Chronic / drug therapy
Hepatitis C, Chronic / psychology
Humans
Interferon-alpha / adverse effects*
MAP Kinase Signaling System / drug effects
Male
Mice
Middle Aged
Neuronal Plasticity / drug effects
Neurons / drug effects
Neurons / metabolism
Neurons / pathology
Poly I-C / pharmacology
STAT1 Transcription Factor / metabolism
STAT3 Transcription Factor / metabolism
Suicide*
Toll-Like Receptor 3 / agonists
Toll-Like Receptor 3 / metabolism*
Up-Regulation / drug effects
Young Adult

Substances

Cytokines
Interferon-alpha
STAT1 Transcription Factor
STAT3 Transcription Factor
Stat1 protein, mouse
Stat3 protein, mouse
TLR3 protein, human
TLR3 protein, mouse
Toll-Like Receptor 3
Poly I-C

Grants and funding

Jörg F Schlaak was supported by the Deutsche Forschungsgemeinschaft (SCHL377/2-2 & 6-2, TRR60). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.