Abstract
Retinoic acid (RA)-producing dendritic cells (DCs) play critical roles in gut immunity. Retinal dehydrogenase 2 (RALDH2) encoded by Aldh1a2 is a key enzyme for generating RA in DCs. Granulocyte–macrophage colony-stimulating factor (GM-CSF) potently induces RALDH2 expression in DCs in an RA-dependent manner, and RA alone weakly induces the expression. However, how GM-CSF and RA induce RALDH2 expression remains unclear. Here, we show that GM-CSF-induced activation of the transcription factor Sp1 and RA-dependent signaling via the RA receptor (RAR)/retinoid X receptor (RXR) complex contribute to Aldh1a2 expression. The RAR antagonist LE540 and the Sp1 inhibitor mithramycin A inhibited GM-CSF-induced Aldh1a2 expression in fms-related tyrosine kinase 3 ligand-generated bone marrow-derived DCs (BM-DCs). ERK and p38 MAPK inhibitors suppressed GM-CSF-induced nuclear translocation of Sp1 and Aldh1a2 expression. Sp1 and the RARα/RXRα complex bound to GC-rich Sp1-binding sites and an RA response element (RARE) half-site, respectively, near the TATA box in the mouse Aldh1a2 promoter. The DNA sequences around these sites were highly conserved among different species. In the presence of RA, ectopic expression of RARα/RXRα and Sp1 synergistically enhanced Aldh1a2 promoter-reporter activity. GM-CSF did not significantly induce Aldh1a2 expression in plasmacytoid DCs, peritoneal macrophages, or T cells, and the Aldh1a2 promoter in these cells was mostly unmethylated. These results suggest that GM-CSF/RA-induced RALDH2 expression in DCs requires cooperative binding of Sp1 and the RAR/RXR complex to the Aldh1a2 promoter, and can be regulated by a DNA methylation-independent mechanism.
Highlights
Dendritic cells (DCs) in gut-related lymphoid organs, mesenteric lymph nodes (MLNs) and Peyer’s patches, produce the vitamin A metabolite retinoic acid (RA), and thereby imprint gut-homing specificity on lymphocytes by inducing or enhancing the expression of the gut-homing receptors, integrin a4b7 and the chemokine receptor CCR9 [1]
We found that the RA receptor (RAR)/retinoid X receptor (RXR) complex bound to an RA response element (RARE) half-site located near the TATA box in the mouse Aldh1a2 promoter
The results of the present study indicated that the binding of Sp1 and RARa/RXRa to a GC-rich region and an RARE halfsite, respectively, in a short 59-flanking region of the TATA box was critical for the granulocyte–macrophage colony-stimulating factor (GM-CSF)/RA-dependent induction of Aldh1a2 expression
Summary
Dendritic cells (DCs) in gut-related lymphoid organs, mesenteric lymph nodes (MLNs) and Peyer’s patches, produce the vitamin A metabolite retinoic acid (RA), and thereby imprint gut-homing specificity on lymphocytes by inducing or enhancing the expression of the gut-homing receptors, integrin a4b7 and the chemokine receptor CCR9 [1]. Because an RA receptor (RAR) a isoform deficiency limits fundamental T cell signaling [10], basal levels of RA may be essential for T-cell activation and the subsequent development of effector T cells. DCs in MLNs, Peyer’s patches, and the lamina propria (LP) of the small intestine express the RA-producing enzyme retinal dehydrogenase 2 (RALDH2) encoded by Aldh1a2 [1,8,11]. High RALDH2 activity levels have been found in a CD103+ mature conventional DC (cDC) subset of MLN-DCs [11,12]. The molecular mechanism underlying the induction of RALDH2 expression remains unclear
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