The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes

Abstract

The two subtypes of retinoid Z receptor (RZR α and β) and the three splicing variants of retinoid orphan receptor (ROR α1, α2, and α3) 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 RZRα and RZRβ. Ligand-induced transcriptional control is therefore proposed to mediate physiological functions of melatonin in the brain where RZRβ is expressed, but also in peripheral tissues, where RZRα 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 RZRα and RORα1, but not RORα2 and α3. 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 RZRα. In contrast, 5-lipoxygenase mRNA levels were not affected in differentiated monocytic and granulocytic cell lines, which do not express RZRα. This indicates that 5-lipoxygenase is the first natural RZRα responding gene. Furthermore, our results open up a new perspective in understanding the involvement of melatonin in inflammatory and immunological reactions.