Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial-macrophage crosstalk

J Innate Immun. 2015;7(1):87-101. doi: 10.1159/000365417. Epub 2014 Aug 20.

Abstract

In the intestine, interaction between epithelial cells and macrophages (MΦs) create a unique immunoregulatory microenvironment necessary to maintain local immune and tissue homeostasis. Human intestinal epithelial cells (IECs) have been shown to express interleukin (IL)-10, which keeps epithelial integrity. We have demonstrated that bacterial signaling through Toll-like receptor (TLR) 4 induces 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) synthesis in intestinal MΦs by cyclooxygenase (Cox)-2 expression. Here, we show that TLR4 signaling generates crosstalk between IECs and MΦs that enhances IL-10 expression in IECs. Direct stimulation of TLR4 leads to the expression of IL-10 in IECs, while the presence of MΦs in a Transwell system induces another peak in IL-10 expression in IECs at a later time point. The second peak of the IL-10 expression is two times greater than the first peak. This late induction of IL-10 depends on the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ that is accumulated in IECs by TLR4-mediated inhibition of the ubiquitin-proteasomal pathway. TLR4 signaling in MΦs in turn synthesizes 15d-PGJ2 through p38 and ERK activation and Cox-2 induction, which activates PPARγ in IECs. These results suggest that TLR4 signaling maintains IL-10 production in IECs by generating epithelial-MΦs crosstalk, which is an important mechanism in the maintenance of intestinal homeostasis mediated through host-bacterial interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Communication / immunology*
  • Cells, Cultured
  • Cyclooxygenase 2 / immunology
  • Epithelial Cells / immunology*
  • Gene Expression Regulation, Enzymologic / immunology
  • Humans
  • Interleukin-10 / immunology*
  • Intestinal Mucosa / immunology*
  • MAP Kinase Signaling System / immunology*
  • Macrophages / immunology*
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / immunology
  • Toll-Like Receptor 4 / immunology*

Substances

  • 15-deoxyprostaglandin J2
  • IL10 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Interleukin-10
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin D2