Abstract
The contribution of Th1 and Th17 cells in chronic inflammatory conditions leading to autoimmunity remains highly controversial. In inflamed tissues, production of prostaglandins by COX-2 has been proposed to favor Th17 responses indirectly by increasing IL-23 and blocking IL-12 release from APC. We report here that prostaglandin E2 (PGE2) can directly modulate cytokine production by human memory CD4(+) T cells. TCR triggering in the presence of PGE2 increased IL-17 and reduced IFN-gamma production by freshly isolated memory T cells or T-cell clones. PGE2 triggered the EP2 and EP4 receptors expressed on T cells leading to a rapid increase of retinoic-acid-related orphan receptor-gammat (ROR-gammat) and decrease of T-cell-specific T-box transcription factor 21 (T-bet) mRNA. Moreover, PGE2 promoted the selective enrichment of IL-17-producing cells by differentially modulating the proliferation of memory T-cell subsets in vitro. Taken together our results indicate that T-cell effector function is a direct target for PGE2 modulation and suggest a novel mechanism by which inhibitors of prostaglandin synthesis, such as COX-2 inhibitors, exert their anti-inflammatory effect.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Autoimmunity / drug effects
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Autoimmunity / immunology
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CD4-Positive T-Lymphocytes / drug effects*
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CD4-Positive T-Lymphocytes / immunology*
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Dinoprostone / immunology
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Dinoprostone / pharmacology*
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Humans
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Immunologic Memory / immunology
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interferon-gamma / immunology*
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Interleukin-17 / antagonists & inhibitors
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Interleukin-17 / biosynthesis
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Nuclear Receptor Subfamily 1, Group F, Member 3
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Prostaglandin E / immunology
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / immunology
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Receptors, Thyroid Hormone / genetics
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Receptors, Thyroid Hormone / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology*
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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Th1 Cells / drug effects
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Th1 Cells / immunology
Substances
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Interleukin-17
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Nuclear Receptor Subfamily 1, Group F, Member 3
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PTGER2 protein, human
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PTGER4 protein, human
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RNA, Messenger
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RORC protein, human
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP2 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Interferon-gamma
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Dinoprostone