title: STAT3 controls IL6-dependent regulation of serotonin transporter function and depression-like behavior.
abstract: Experimental evidence suggests a role for the immune system in the pathophysiology of depression. A specific involvement of the proinflammatory cytokine interleukin 6 (IL6) in both, patients suffering from the disease and pertinent animal models, has been proposed. However, it is not clear how IL6 impinges on neurotransmission and thus contributes to depression. Here we tested the hypothesis that IL6-induced modulation of serotonergic neurotransmission through the STAT3 signaling pathway contributes to the role of IL6 in depression. Addition of IL6 to JAR cells, endogenously expressing SERT, reduced SERT activity and downregulated SERT mRNA and protein levels. Similarly, SERT expression was reduced upon IL6 treatment in the mouse hippocampus. Conversely, hippocampal tissue of IL6-KO mice contained elevated levels of SERT and IL6-KO mice displayed a reduction in depression-like behavior and blunted response to acute antidepressant treatment. STAT3 IL6-dependently associated with the SERT promoter and inhibition of STAT3 blocked the effect of IL6 in-vitro and modulated depression-like behavior in-vivo. These observations demonstrate that IL6 directly controls SERT levels and consequently serotonin reuptake and identify STAT3-dependent regulation of SERT as conceivable neurobiological substrate for the involvement of IL6 in depression.
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Eryan
authors.initials: E
authors.lastname: Kong
authors.affiliation: Department of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Sonja
authors.initials: S
authors.lastname: Sucic
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Monje
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Savalli
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Weifei
authors.initials: W
authors.lastname: Diao
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Deeba
authors.initials: D
authors.lastname: Khan
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ronovsky
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Maureen
authors.initials: M
authors.lastname: Cabatic
authors.affiliation: Department of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Florian
authors.initials: F
authors.lastname: Koban
authors.affiliation: Department of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna.
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Pollak
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002460:Cell Line; D003863:Depression / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin