Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4

Mucosal Immunol. 2009 May;2(3):254-64. doi: 10.1038/mi.2009.2. Epub 2009 Mar 4.

Abstract

Oral intake of protein leads to tolerance through the induction of regulatory T cells (Tr cells) in mesenteric lymph nodes (MLNs). Here we show that the inhibition of cyclooxygenase-2 (COX-2) in vivo suppressed oral tolerance and was associated with enhanced differentiation of interleukin (IL)-4-producing T cells and reduced Foxp3(+) Tr-cell differentiation in MLN. As a result, the functional suppressive capacity of these differentiated mucosal T cells was lost. IL-4 was causally related to loss of tolerance as treatment of mice with anti-IL-4 antibodies during COX-2 inhibition restored tolerance. Dendritic cells (DCs) in the MLN differentially expressed COX-2 and reductionist experiments revealed that selective inhibition of the enzyme in these cells inhibited Foxp3(+) Tr-cell differentiation in vitro. Importantly, the inhibition of COX-2 in MLN-DC caused increased GATA-3 expression and enhanced IL-4 release by T cells, which was directly related to impaired Tr-cell differentiation. These data provide crucial insights into the mechanisms driving de novo Tr-cell induction and tolerance in the intestine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acid / pharmacology
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / immunology*
  • Cyclooxygenase Inhibitors / pharmacology
  • Cytokines / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / enzymology*
  • Dendritic Cells / immunology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Immune Tolerance
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / immunology*
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Nitrobenzenes / pharmacology
  • Ovalbumin / immunology
  • Sulfonamides / pharmacology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Cyclooxygenase Inhibitors
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Nitrobenzenes
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Interleukin-4
  • Arachidonic Acid
  • Ovalbumin
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2