Steinhilber D, Brungs M, Werz O, Wiesenberg I, Danielsson C, Kahlen J P, Nayeri S, Schräder M, Carlberg C
Pharmazeutisches Institut, Universität Tübingen, Germany.
J Biol Chem. 1995 Mar 31;270(13):7037-40. doi: 10.1074/jbc.270.13.7037.
The two subtypes of retinoid Z receptor (RZR alpha and beta) and the three splicing variants of retinoid orphan receptor (ROR alpha 1, alpha 2, and alpha 3) form a subfamily within the superfamily of nuclear hormone receptors. Very recently we found that the pineal gland hormone melatonin is a natural ligand of RZR alpha and RZR beta. Ligand-induced transcriptional control is therefore proposed to mediate physiological functions of melatonin in the brain where RZR beta is expressed, but also in peripheral tissues, where RZR alpha was found. However, no natural RZR responding genes have been identified yet. Here, we report that a response element in the promoter of 5-lipoxygenase binds specifically RZR alpha and ROR alpha 1, but not ROR alpha 2 and alpha 3. 5-Lipoxygenase is a key enzyme in the biosynthesis of leukotrienes, which are known to be allergic and inflammatory mediators. We could show that the activity of the whole 5-lipoxygenase promoter as well as of the RZR response element fused to the heterologous thymidine kinase promoter could be repressed by melatonin. The hormone down-regulated the expression of 5-lipoxygenase about 5-fold in B lymphocytes, which express RZR alpha. In contrast, 5-lipoxygenase mRNA levels were not affected in differentiated monocytic and granulocytic cell lines, which do not express RZR alpha. This indicates that 5-lipoxygenase is the first natural RZR alpha responding gene. Furthermore, our results open up a new perspective in understanding the involvement of melatonin in inflammatory and immunological reactions.
类视黄醇Z受体的两种亚型（RZRα和β）以及类视黄醇孤儿受体的三种剪接变体（RORα1、α2和α3）在核激素受体超家族中形成一个亚家族。最近我们发现，松果体激素褪黑素是RZRα和RZRβ的天然配体。因此，有人提出配体诱导的转录调控介导褪黑素在表达RZRβ的脑内以及在发现RZRα的外周组织中的生理功能。然而，尚未鉴定出天然的RZR反应基因。在此，我们报告5-脂氧合酶启动子中的一个反应元件特异性结合RZRα和RORα1，但不结合RORα2和α3。5-脂氧合酶是白三烯生物合成中的关键酶，已知白三烯是过敏和炎症介质。我们能够证明，整个5-脂氧合酶启动子以及与异源胸苷激酶启动子融合的RZR反应元件的活性可被褪黑素抑制。该激素使表达RZRα的B淋巴细胞中5-脂氧合酶的表达下调约5倍。相比之下，在不表达RZRα的分化单核细胞和粒细胞系中，5-脂氧合酶mRNA水平不受影响。这表明5-脂氧合酶是第一个天然的RZRα反应基因。此外，我们的结果为理解褪黑素在炎症和免疫反应中的作用开辟了新的视角。
