title: 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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Carolina
authors.initials: C
authors.lastname: Hoyo-Becerra
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Huebener
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lutterbeck
authors.affiliation: Department of Anatomy, Tongji Medical College of Huazhong, University of Science and Technology, Wuhan City, P.R.China.
authors.forename: Zijian J
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Institute for Forensic Medicine, University Hospital of Essen, Essen, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Truebner
authors.affiliation: Institute for Forensic Medicine, University Hospital of Essen, Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bajanowski
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.affiliation: Department of Neurology, University Hospital of Essen, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D003863:Depression / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000523:psychology; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013405:Suicide; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C