The Journal of Experimental Medicine
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Published online 8 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/413/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 3, August 7, 2000 413-420

Original Article

Cell-specific Transcriptional Regulation of Human Leukotriene B4 Receptor Gene

Kazuhiko Katoa,c, Takehiko Yokomizoa,b, Takashi Izumia,b, and Takao Shimizua,b
a Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
b Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Tokyo 113-0033, Japan
c Pharmaceutical Research Center, Meiji Seika Kaisha, Limited, Yokohama 222-8567, Japan

Correspondence to: Takao Shimizu, Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Tel:81-3-5802-2925 Fax:81-3-3813-8732 E-mail:tshimizu{at}m.u-tokyo.ac.jp.

Leukotriene B4 (LTB4) is a lipid mediator that activates leukocytes and is involved in host defense and inflammation. BLT1, a high-affinity receptor for LTB4 (originally termed BLT), is expressed exclusively in inflammatory cells and is inducible in macrophages upon activation. The mechanisms of tissue-specific expression and induction of BLT1 are important for the understanding of mechanism of onset and the potential treatment of inflammatory disorders. Here, we report the genomic structure and a promoter analysis of the human BLT1 gene, with an emphasis on the mechanism of cell-specific transcription. No TATA or CAAT elements exist around the transcription initiation sites, but a GC-rich sequence is observed in this region. A reporter gene assay revealed that a region ~80 basepair upstream from the initiator sequence is required for the basal transcription of the BLT1 gene. Sp1 was found to be a major activator of basal transcription by electrophoretic mobility shift assays and site-directed mutagenesis. The CpG sites of the BLT1 promoter region were highly methylated in BLT1-nonexpressing cells, but not methylated in BLT1-expressing cells. Further, methylation of this region in vitro inhibited the promoter activity to ~15% of the control. Thus, methylation at CpG sites in the promoter region is important for cell-specific transcription of the BLT1 gene. The promoter region of the BLT1 gene is localized within the open reading frame (ORF) of the BLT2 gene, which encodes a low-affinity receptor for LTB4 (Yokomizo, T., K. Kato, K. Terawaki, T. Izumi, and T. Shimizu. 2000. J. Exp. Med. 192:421–431). To our knowledge, this is the first example of "promoter in ORF" in higher eukaryotes.

Key Words: leukotriene B4 receptor, inflammation, methylation, Sp1, THP-1 cell


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