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Functional Characterization of Human Cysteinyl Leukotriene 1 Receptor Gene Structure¹

Grzegorz Woszczek^*, Rafal Pawliczak^*,, Hai-Yan Qi^*, Sahrudaya Nagineni^*, Sura Alsaaty^*, Carolea Logun^* and James H. Shelhamer^2,*

^* Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892; and Department of Immunopathology, Medical University of Lodz, Lodz, Poland

The 5-lipoxygenase pathway has been strongly implicated in the pathogenesis of chronic inflammatory disorders, such as bronchial asthma and atherosclerosis. Cysteinyl leukotrienes (cysLTs), 5-lipoxygenase pathway products, are recognized now not only as important factors in asthmatic inflammation, but also as mediators of cell trafficking and innate immune responses. To study a role of cysLTs in inflammatory reactions we have characterized the gene structure of human cysteinyl leukotriene receptor type I (cysLT₁R). The cysLT₁R gene consists of 5 exons that are variably spliced and a single promoter region with multiple transcription start sites. Four different cysLT₁R transcripts were identified. RT-PCR showed dominant and wide expression of the transcript I, containing exons 1, 4, and 5, with the strongest presence in blood leukocytes, spleen, thymus, lung, and heart. The expression of cysLT₁R is functionally regulated at the transcriptional level by IL-4 through a STAT6 response element localized to the proximal cysLT₁R promoter region. IL-4 stimulation increased cysLT₁R mRNA (real-time PCR) and surface protein expression (flow cytometry) in a time-dependent fashion. CysLTs (LTD₄ and LTC₄) induced an increased production of a potent monocyte chemoattractant CCL2 (MCP-1) in IL-4-primed THP-1 cells in a dose-dependent manner. This effect was effectively inhibited by the cysLT₁R-selective antagonist MK571 in a dose-dependent manner and only partially by a nonselective cysLT₁R/cysLT₂R inhibitor BAY-u9773, implying a cysLT₁R-mediated mechanism. Thus, cysLTs signaling through cysLT₁R might contribute to inflammatory reactions by cooperating with IL-4 in enhanced CCL2 production in human monocytic cells.

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