title: Elevation of Il6 is associated with disturbed let-7 biogenesis in a genetic model of depression.
abstract: Elevation of the proinflammatory cytokine IL-6 has been implicated in depression; however, the mechanisms remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression post-transcriptionally. The lethal-7 (let-7) miRNA family was suggested to be involved in the inflammation process and IL-6 was shown to be one of its targets. In the present study, we report elevation of Il6 in the prefrontal cortex (PFC) of a genetic rat model of depression, the Flinders Sensitive Line (FSL) compared to the control Flinders Resistant Line. This elevation was associated with an overexpression of LIN28B and downregulation of let-7 miRNAs, the former an RNA-binding protein that selectively represses let-7 synthesis. Also DROSHA, a key enzyme in miRNA biogenesis was downregulated in FSL. Running was previously shown to have an antidepressant-like effect in the FSL rat. We found that running reduced Il6 levels and selectively increased let-7i and miR-98 expression in the PFC of FSL, although there were no differences in LIN28B and DROSHA expression. Pri-let-7i was upregulated in the running FSL group, which associated with increased histone H4 acetylation. In conclusion, the disturbance of let-7 family biogenesis may underlie increased proinflammatory markers in the depressed FSL rats while physical activity could reduce their expression, possibly through regulating primary miRNA expression via epigenetic mechanisms.
authors.affiliation: Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Y B
authors.initials: YB
authors.lastname: Wei
authors.affiliation: Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J J
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Neurogenetics Unit, Department of Molecular Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J C
authors.initials: JC
authors.lastname: Villaescusa
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Åberg
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Brené
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.|Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.
authors.forename: G
authors.initials: G
authors.lastname: Wegener
authors.affiliation: Section for Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A A
authors.initials: AA
authors.lastname: Mathé
authors.affiliation: Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Lavebratt
mesh_terms: D000818:Animals; D003863:Depression / Q000235:genetics*; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D015850:Interleukin-6; C578027:Lin28A protein, rat; C571630:MIRN98 microRNA-98, rat; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C000624624:Drosha protein, rat; D043244:Ribonuclease III