Retinoic Acid and GM-CSF Coordinately Induce Retinal Dehydrogenase 2 (RALDH2) Expression through Cooperation between the RAR/RXR Complex and Sp1 in Dendritic Cells

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.

A genome‐wide association study suggests several novel candidate genes for carcass traits in Chinese Simmental beef cattle

“…ALDH1A2 ( aldehyde dehydrogenase 1 family member A2 ), also known as RALDH2 , has been identified to play critical roles in the synthesis of retinoic acid, the active derivative of vitamin A (retinol), which affects mainly body growth and bone development in animals (Ohoka et al . ). FAM84B ( family with sequence similarity 84 member B ) has been suggested as a candidate gene for poor sperm motility in Holstein–Friesian bulls (Hering et al .…”

Differential regulation of CD103 (αE integrin) expression in human dendritic cells by retinoic acid and Toll-like receptor ligands

“…RA is known to enhance RA biosynthesis in murine DCs through a positive-feedback loop [26][27][28]. We previously showed that exposure of human blood monocytes to RA-producing gastric epithelial cells or RA drives RA biosynthesis in the monocytes.…”

Genetic contribution of retinoid-related genes to neural tube defects

“…Figure 1D-F). It is interesting that these are all experimental-based RA-responsive genes with RARE binding sites located in their upstream regionsLoudig et al, 2000;Ohoka, Yokota-Nakatsuma, Maeda, Takeuchi, & Iwata, 2014) or RXR binding sites predicted by PROMO(Farre et al, 2003;Messeguer et al, 2002) (Figure 1D-F). Although the genomic distances between clustered NTD-specific rare variants and RAREs are about 130 bp (ALDH1A2), 1294 bp (CYP26A1), and 1,664 bp (CRABP1) (Figure 1D-F), it is possible that the NTD-specific rare variants could…”