title: Prostaglandin E2 suppresses the differentiation of retinoic acid-producing dendritic cells in mice and humans.
abstract: The production of retinoic acid (RA) by dendritic cells (DCs) is critical for the induction of gut-tropic immune responses by driving the expression of intestinal-specific homing receptors, such as α4β7 and CCR9, upon T and B cell activation. However, how RA production is regulated during DC development remains unclear. We describe an unexpected role for prostaglandin E2 (PGE2) as a negative regulator of retinal dehydrogenases (RALDH), the enzymes responsible for RA synthesis. The presence of PGE2 during DC differentiation inhibited RALDH expression in mouse and human DCs, abrogating their ability to induce CCR9 expression upon T cell priming. Furthermore, blocking PGE2 signaling increased the frequency of RALDH(+) DCs in vitro, and reducing PGE2 synthesis in vivo promoted the systemic emergence of RA-producing DCs and the priming of CCR9(+) T cells in nonintestinal sites such as the spleen. Finally, we found that PGE2 stimulated the expression of the inducible cyclic AMP early repressor, which appears to directly inhibit RALDH expression in DCs, thus providing mechanistic insight into how PGE2 signaling down-modulates RALDH. Given the role of PGE2 in regulating the development of RA-producing DCs, modulating this pathway may prove a novel means to control the development of gut-tropic immune responses.
authors: Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, England, UK.
authors: Angus
authors: A
authors: Stock
authors: Sarah
authors: S
authors: Booth
authors: Vincenzo
authors: V
authors: Cerundolo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology*; D015232:Dinoprostone / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000502:physiology; D050697:Retinal Dehydrogenase / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C497411:Crem protein, mouse; D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051786:Cyclic AMP Response Element Modulator; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050697:Retinal Dehydrogenase; D015232:Dinoprostone