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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arachidonic Acid / pharmacology
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Cell Differentiation / physiology
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Cells, Cultured
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Cyclooxygenase 2 / biosynthesis
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Cyclooxygenase 2 / immunology*
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Cyclooxygenase Inhibitors / pharmacology
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Cytokines / immunology
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Dendritic Cells / drug effects
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Dendritic Cells / enzymology*
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Dendritic Cells / immunology
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism
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Immune Tolerance
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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / biosynthesis
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Interleukin-4 / immunology*
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Intestinal Mucosa / cytology
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / metabolism
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Lymphocyte Activation
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Mice
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Mice, Inbred BALB C
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Nitrobenzenes / pharmacology
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Ovalbumin / immunology
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Sulfonamides / pharmacology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology*
Substances
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Cyclooxygenase Inhibitors
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Cytokines
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Nitrobenzenes
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Sulfonamides
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Interleukin-4
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Arachidonic Acid
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Ovalbumin
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Ptgs2 protein, mouse
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Cyclooxygenase 2