The nuclear receptor for melatonin represses 5-lipoxygenase gene expression in human B lymphocytes.
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.
Steinhilber
D
D
Pharmazeutisches Institut, Universität Tübingen, Germany.
Brungs
M
M
Werz
O
O
Wiesenberg
I
I
Danielsson
C
C
Kahlen
J P
JP
Nayeri
S
S
Schräder
M
M
Carlberg
C
C
D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology; D004794:Enzyme Repression / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008550:Melatonin / Q000494:pharmacology; D008969:Molecular Sequence Data; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004268:DNA-Binding Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D001094:Arachidonate 5-Lipoxygenase; D008550:Melatonin