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Gastroenterology. 2011 Jul;141(1):176-85. doi: 10.1053/j.gastro.2011.04.010. Epub 2011 Apr 16.

MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells.

Author information

1
Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

Abstract

BACKGROUND & AIMS:

Gut-associated dendritic cells (DC) metabolize vitamin A into all-trans retinoic acid (RA), which is required to induce lymphocytes to localize to the gastrointestinal tract and promotes the differentiation of Foxp3+ regulatory T cells and IgA antibody-secreting cells. We investigated whether RA functions in a positive-feedback loop in DC to induce its own synthesis.

METHODS:

We measured levels of retinoids in intestinal tissues from mice and assessed the role of RA in the functional specialization of gut-associated DC in cell cultures and mice. We used pharmacologic antagonists to determine the signaling pathways involved in regulation of DC and used MyD88-/- mice to determine the contribution of Toll-like receptor signaling in RA-mediated effects on DC.

RESULTS:

The concentration of retinoids decreased in a proximal-to-distal gradient along the intestine, which correlated with the activity of gut-specific DC. Importantly, RA regulated the ability of gut-associated DC to produce RA, induce T cells to localize to the gastrointestinal tract, and generate regulatory T cells and IgA-secreting cells. RA was sufficient to induce its own production by extraintestinal DC in vitro and in vivo. RA-mediated regulation of DC required signaling through the mitogen-activated protein kinase signaling pathway and unexpectedly required MyD88, which is conventionally associated with Toll-like receptor, interleukin-1, and interleukin-18 signaling.

CONCLUSIONS:

RA is necessary and sufficient to induce DC to regulate T-cell localization to the gastrointestinal tract and IgA secretion. Our findings also indicate crosstalk between the RA receptor and MyD88-dependent Toll-like receptor signaling pathways.

PMID:
21596042
PMCID:
PMC3129445
DOI:
10.1053/j.gastro.2011.04.010
[Indexed for MEDLINE]
Free PMC Article

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