IL-17A signaling in colonic epithelial cells inhibits pro-inflammatory cytokine production by enhancing the activity of ERK and PI3K

PLoS One. 2014 Feb 25;9(2):e89714. doi: 10.1371/journal.pone.0089714. eCollection 2014.

Abstract

Our previous data suggested that IL-17A contributes to the inhibition of Th1 cell function in the gut. However, the underlying mechanisms remain unclear. Here we demonstrate that IL-17A signaling in colonic epithelial cells (CECs) increases TNF-α-induced PI3K-AKT and ERK phosphorylation and inhibits TNF-α induced expression of IL-12P35 and of a Th1 cell chemokine, CXCL11 at mRNA level. In a co-culture system using HT-29 cells and PBMCs, IL-17A inhibited TNF-α-induced IL-12P35 expression by HT-29 cells and led to decreased expression of IFN-γ and T-bet by PBMCs. Finally, adoptive transfer of CECs from mice with Crohn's Disease (CD) led to an enhanced Th1 cell response and exacerbated colitis in CD mouse recipients. The pathogenic effect of CECs derived from CD mice was reversed by co-administration of recombinant IL-17A. Our data demonstrate a new IL-17A-mediated regulatory mechanism in CD. A better understanding of this pathway might shed new light on the pathogenesis of CD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Androstadienes / pharmacology
  • Animals
  • Butadienes / pharmacology
  • Chemokine CXCL11 / antagonists & inhibitors
  • Coculture Techniques
  • Colitis / metabolism
  • Colon
  • Cytokines / metabolism
  • Epithelial Cells / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • HT29 Cells
  • Humans
  • Interleukin-12 Subunit p35
  • Interleukin-17 / physiology*
  • Mice, Inbred BALB C
  • Nitriles / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Signal Transduction / physiology*
  • Th1 Cells / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Wortmannin

Substances

  • Adaptor Proteins, Signal Transducing
  • Androstadienes
  • Butadienes
  • Chemokine CXCL11
  • Cytokines
  • Interleukin-12 Subunit p35
  • Interleukin-17
  • Nitriles
  • Traf3ip2 protein, mouse
  • Tumor Necrosis Factor-alpha
  • U 0126
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Wortmannin

Grants and funding

This work was supported by a National “973” Fund (grant number 2013CB530506), and the National Natural Sciences Foundation of China (grants 81072475, 81172800, and 31100961). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.