The Journal of Experimental Medicine
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Published online 18 September 2006 doi:10.1084/jem.20060141
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 10, 2351-2362
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ARTICLE

 PPAR{gamma} controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells

Istvan Szatmari1, Attila Pap1, Ralph Rühl1, Jiang-Xing Ma4, Petr A. Illarionov5, Gurdyal S. Besra5, Eva Rajnavolgyi2, Balazs Dezso3, and Laszlo Nagy1

1 Department of Biochemistry and Molecular Biology, 2 Department of Immunology, and 3 Department of Pathology, University of Debrecen, Medical and Health Science Center, Debrecen H-4010, Hungary
4 Department of Cell Biology and Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
5 School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

CORRESPONDENCE: Laszlo Nagy: lnagy{at}indi.biochem.dote.hu

Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR){gamma}, indirectly regulates CD1d expression. Here we demonstrate that PPAR{gamma}, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPAR{gamma}-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR){alpha} in human DCs, and RAR{alpha} acutely regulates CD1d expression. The retinoic acid–induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPAR{gamma}-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression.

Abbreviations used: ADH, alcohol dehydrogenase; ATRA, all-trans retinoic acid; DEAB, 4-diethyl amino-benzaldehyde; FABP, fatty acid–binding protein; GGC, galactosyl(a1-2) galactosyl-ceramide; IHC, immunohistochemistry; LC-MS, liquid chromatography–mass spectrometry; MDC, mature DC; MLR, mixed leukocyte reaction; oxLDL, oxidized low density lipoprotein; PPAR, peroxisome proliferator-activated receptor; RALDH, retinaldehyde dehydrogenase; RAR, retinoic acid receptor; RDH, retinol dehydrogenase; RSG, rosiglitazone; RT-Q-PCR, real-time quantitative PCR; RXR, retinoid X receptor; SDR, short-chain dehydrogenase/reductase; TGM, transglutaminase.


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