ERK differentially regulates Th17- and Treg-cell development and contributes to the pathogenesis of colitis

Eur J Immunol. 2013 Jul;43(7):1716-26. doi: 10.1002/eji.201242889. Epub 2013 Jun 3.


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.

Keywords: Colitis; ERK; Th17; Treg.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / immunology
  • Colitis / immunology*
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases / immunology*
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / cytology
  • Th17 Cells / immunology*
  • Transfection


  • Enzyme Inhibitors
  • RNA, Small Interfering
  • Extracellular Signal-Regulated MAP Kinases