title: MicroRNA-146a controls Th1-cell differentiation of human CD4+ T lymphocytes by targeting PRKCε.
abstract: T-cell functions must be tightly controlled to keep the balance between vital proinflammatory activity and detrimental overactivation. MicroRNA-146a (miR-146a) has been identified as a key negative regulator of T-cell responses in mice. Its role in human T cells and its relevance to human inflammatory disease, however, remains poorly defined. In this study, we have characterized miR-146a-driven pathways in primary human T cells. Our results identify miR-146a as a critical gatekeeper of Th1-cell differentiation processes acting via molecular mechanisms not uncovered so far. MiR-146a targets protein kinase C epsilon (PRKCε), which is part of a functional complex consisting of PRKCε and signal transducer and activator of transcription 4 (STAT4). Within this complex, PRKCε phosphorylates STAT4, which in turn is capable of promoting Th1-cell differentiation processes in human CD4(+) T lymphocytes. In addition, we observed that T cells of sepsis patients had reduced levels of miR-146a and an increased PRKCε expression in the initial hyperinflammatory phase of the disease. Collectively, our results identify miR-146a as a potent inhibitor of Th1-cell differentiation in human T cells and suggest that dysregulation of miR-146a contributes to the pathogenesis of sepsis.
authors.affiliation: Research Group Molecular Medicine, Department of Anesthesiology, University of Munich (LMU), Munich, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Möhnle
authors.forename: Stefanie V
authors.initials: SV
authors.lastname: Schütz
authors.forename: Verena
authors.initials: V
authors.lastname: van der Heide
authors.forename: Max
authors.initials: M
authors.lastname: Hübner
authors.forename: Benjamin
authors.initials: B
authors.lastname: Luchting
authors.forename: Julia
authors.initials: J
authors.lastname: Sedlbauer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Limbeck
authors.forename: Ludwig C
authors.initials: LC
authors.lastname: Hinske
authors.forename: Josef
authors.initials: J
authors.lastname: Briegel
authors.forename: Simone
authors.initials: S
authors.lastname: Kreth
mesh_terms: D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D010766:Phosphorylation; D061251:Primary Cell Culture; D051744:Protein Kinase C-epsilon / Q000235:genetics* / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000276:immunology; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D051744:Protein Kinase C-epsilon
keywords: CD4+ T cells; Cell differentiation; Gene regulation; Inflammation; MicroRNA