Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+ T cells.
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.
Napolitani
Giorgio
G
Institute for Research in Biomedicine, Bellinzona, Switzerland. giorgio.napolitani@irb.unisi.ch
Acosta-Rodriguez
Eva V
EV
Lanzavecchia
Antonio
A
Sallusto
Federica
F
D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D015232:Dinoprostone / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000276:immunology; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D000098815:T-bet Transcription Factor
D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D012333:RNA, Messenger; C539900:RORC protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D015232:Dinoprostone