The Nuclear Receptor for Melatonin Represses 5-Lipoxygenase Gene Expression in Human B Lymphocytes

doi:10.1074/jbc.270.13.7037

The Nuclear Receptor for Melatonin Represses 5-Lipoxygenase Gene Expression in Human B Lymphocytes (*)

From the (1)Pharmazeutisches Institut der Universität Tübingen, D-72076 Tübingen, Germany,
(2)Pharma-Forschung, Ciba-Geigy AG, CH-4002 Basel, Switzerland, and
(3)Clinique de Dermatologie, Hôpital Cantonal Universitaire, CH-1211 Genève 14, Switzerland

^§ To whom correspondence should be addressed. Tel.: 41-22-37-29428; Fax: 41-22-37-29460.

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.

Footnotes

↵* This work was supported by Swiss National Foundation Grant 3100-040314.94 (to C. C.) and Deutsche Forschungsgemeinschaft Grant 458/2-1 (to D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

RZR

retinoid Z receptor

ROR

RAR-related orphan receptor

TGF

transforming growth factor

CAT

chloramphenicol acetyltransferase

PCR

polymerase chain reaction

RT-PCR

reverse transcriptase-PCR

FCS

fetal calf serum

DOTAP

N-[1-(2,3-dioleoyloxy)propyl]-N, N,N-trimethylammonium methylsulfate.
- Received December 23, 1994.
- Revision received January 30, 1995.