Szatmari Istvan, Pap Attila, Rühl Ralph, Ma Jiang-Xing, Illarionov Petr A, Besra Gurdyal S, Rajnavolgyi Eva, Dezso Balazs, Nagy Laszlo
Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Debrecen H-4010, Hungary.
J Exp Med. 2006 Oct 2;203(10):2351-62. doi: 10.1084/jem.20060141. Epub 2006 Sep 18.
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 PPARgamma, 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). PPARgamma-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 RARalpha 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 PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression.
表达CD1d（一种负责脂质抗原呈递的分子）的树突状细胞（DC）能够增强自然杀伤T（iNKT）细胞的增殖。控制CD1表达和脂质抗原呈递的信号目前还不清楚。我们之前已经表明，脂质激活的转录因子过氧化物酶体增殖物激活受体（PPAR）γ的刺激可间接调节CD1d的表达。在此我们证明，PPARγ通过诱导视黄醇和视黄醛代谢酶（如视黄醇脱氢酶10和2型视黄醛脱氢酶（RALDH2））的表达来开启视黄酸的合成。PPARγ对这些酶的表达调控导致视黄醇向全反式视黄酸（ATRA）的细胞内生成增加。ATRA通过激活人类DC中的视黄酸受体（RAR）α来调节基因表达，并且RARα可急性调节CD1d的表达。视黄酸诱导的CD1d表达升高与增强的iNKT细胞活化相关。此外，体内相关脂质如氧化型低密度脂蛋白也可引发类视黄醇信号传导，导致CD1d上调。这些数据表明，类视黄醇代谢和信号传导的调节是DC中PPARγ控制的转录事件的一部分。所揭示的机制使DC能够通过改变CD1基因表达来应对脂质稳态的改变。
