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Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans

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 develop...

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Autores principales: Stock, Angus, Booth, Sarah, Cerundolo, Vincenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135350/
https://www.ncbi.nlm.nih.gov/pubmed/21444662
http://dx.doi.org/10.1084/jem.20101967
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author Stock, Angus
Booth, Sarah
Cerundolo, Vincenzo
author_facet Stock, Angus
Booth, Sarah
Cerundolo, Vincenzo
author_sort Stock, Angus
collection PubMed
description 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.
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spelling pubmed-31353502012-01-11 Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans Stock, Angus Booth, Sarah Cerundolo, Vincenzo J Exp Med Article 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. The Rockefeller University Press 2011-04-11 /pmc/articles/PMC3135350/ /pubmed/21444662 http://dx.doi.org/10.1084/jem.20101967 Text en © 2011 Stock et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Stock, Angus
Booth, Sarah
Cerundolo, Vincenzo
Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
title Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
title_full Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
title_fullStr Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
title_full_unstemmed Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
title_short Prostaglandin E2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
title_sort prostaglandin e2 suppresses the differentiation of retinoic acid–producing dendritic cells in mice and humans
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135350/
https://www.ncbi.nlm.nih.gov/pubmed/21444662
http://dx.doi.org/10.1084/jem.20101967
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