title: ERK differentially regulates Th17- and Treg-cell development and contributes to the pathogenesis of colitis.
abstract: Although the development of T-cell subsets is mainly regulated by a master transcriptional regulator and phosphorylation of the STAT protein in response to distinct cytokine stimulation, accumulating data indicate that other signaling pathways are also involved in regulating or fine-tuning T-cell lineage commitment. In this report, we investigated the role of ERK, mitogen-activated protein kinase (MAPK), in Th17 and Treg cell development. We demonstrate that blockade of ERK activation inhibited Th17-cell development while upregulating Treg cells under Th17 polarization conditions. Inhibition of ERK decreased IL-6 induction of RAR-related orphan receptor γt but enhanced TGF-β induction of Foxp3, and ERK inhibitor-treated T cells under Th17 conditions possessed suppressive function in vitro because they produced more IL-10 and TGF-β and inhibited naïve T-cell proliferation and IFN-γ production at levels comparable with that of Treg cells. Furthermore, ERK inhibitor-treated T cells under Th17 polarization conditions had a decreased potency to induce colitis in vivo. Collectively, our data demonstrated that the ERK pathway differentially regulates Th17- and Treg-cell differentiation, and thus interfering with the ERK pathway could represent a therapeutic treatment for inflammatory bowel diseases and other Th17-related autoimmune diseases.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.
authors.forename: Houpu
authors.initials: H
authors.lastname: Liu
authors.forename: Suxia
authors.initials: S
authors.lastname: Yao
authors.forename: Sara M
authors.initials: SM
authors.lastname: Dann
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.forename: Charles O
authors.initials: CO
authors.lastname: Elson
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003092:Colitis / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Colitis; ERK; Th17; Treg