Interferon-Î³ Up-regulates Expression of Cysteinyl Leukotriene Type 2 Receptors on Eosinophils in Asthmatic Patients

Fujii, Masaru; Tanaka, Hiroshi; Abe, Shosaku

doi:10.1378/chest.128.5.3148

Cited by 44 publications

(33 citation statements)

References 21 publications

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“…However, IFN-␥ has been found to induce CysLT 2 R expression and to enhance the responsiveness to cysteinyl LTs of human ECs (Woszczek et al, 2007), as well as of monocytes, T cells, and B lymphocytes (Early et al, 2007). These data confirm early observations by Fujii et al (2005), who postulated that CysLT 2 R might modulate exacerbations of asthma, as they observed that CysLT 2 R expression on eosinophils was up-regulated by IFN-␥ and increased during asthma exacerbation, especially in nonatopic subjects. In addition, another proinflammatory cytokine, IL-18, has also been recently postulated to upregulate CysT 2 R expression in HUVECs at the early 560 stage of administration, accelerating cell apoptosis .…”

Section: B Cyslt Receptor Expression and Immunoregulationsupporting

confidence: 83%

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

Bäck¹,

Dahlén²,

Drazen³

et al. 2011

Pharmacol Rev

130

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Section: B Cyslt Receptor Expression and Immunoregulationsupporting

confidence: 83%

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

Bäck¹,

Dahlén²,

Drazen³

et al. 2011

Pharmacol Rev

130

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“…For example, such an intronic enhancer was shown to regulate Cox-1 expression in response to PMA (26). In agreement with our observation, it has been shown recently that IFN-␥ can up-regulate CysLTR2 expression in eosinophils, but the mechanism has not been studied (27). It may be hypothesized that the similar mechanism of IFN-␥-mediated enhancement of cysLT signaling may apply to other cells expressing this receptor.…”

Section: Discussionsupporting

confidence: 89%

IFN-γ Induces Cysteinyl Leukotriene Receptor 2 Expression and Enhances the Responsiveness of Human Endothelial Cells to Cysteinyl Leukotrienes

Woszczek

Chen

Nagineni

et al. 2007

The Journal of Immunology

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Cysteinyl leukotrienes (cysLTs) are important mediators of cell trafficking and innate immune responses, involved in the pathogenesis of inflammatory processes, i.e., atherosclerosis, pulmonary fibrosis, and bronchial asthma. The aim of this study was to examine the regulation of cysLT signaling by IFN-γ in human primary endothelial cells. IFN-γ increased cysLT receptor 2 (CysLTR2) mRNA expression and CysLTR2-specific calcium signaling in endothelial cells. IFN-γ signaled through Jak/STAT1, as both AG490, a Jak2 inhibitor, and expression of a STAT1 dominant-negative construct, significantly inhibited CysLTR2 mRNA expression in response to IFN-γ. To determine mechanisms of IFN-γ-induced CysLTR2 expression, the human CysLTR2 gene structure was characterized. The CysLTR2 gene has a TATA-less promoter, with multiple transcription start sites. It consists of six variably spliced exons. Eight different CysLTR2 transcripts were identified in endothelial and monocytic cells. Gene reporter assay showed potent basal promoter activity of a putative CysLTR2 promoter region. However, there were no significant changes in gene reporter and mRNA t1/2 assays in response to IFN-γ, suggesting transcriptional control of CysLTR2 mRNA up-regulation by IFN-γ response motifs localized outside of the cloned CysLTR2 promoter region. Stimulation of endothelial cells by cysLTs induced mRNA and protein expression of early growth response genes 1, 2, and 3 and cycloxygenase-2. This response was mediated by CysLTR2 coupled to Gq/11, activation of phospholipase C, and inositol-1,4,5-triphosphate, and was enhanced further 2- to 5-fold by IFN-γ stimulation. Thus, IFN-γ induces CysLTR2 expression and enhances cysLT-induced inflammatory responses.

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“…In the latter study, IFN-␥ decreased CysLT1 receptor mRNA expression in monocytes, while IFN-␥ stimulated CysLT1 and CysLT2 receptor mRNA production and CysLT1 receptor surface expression on smooth muscle cells (13). IL-5 increased CysLT1 receptor mRNA and cell surface expression on a human eosinophil cell line (19), and recently it has been reported that IFN-␥ increases CysLT2 receptor expression on eosinophils from patients with asthma (20). Together these studies broadly suggest the ability of cytokines associated with allergic inflammation to up-regulate expression of CysLT receptors.…”

Section: Discussionmentioning

confidence: 77%

Concordant Modulation of Cysteinyl Leukotriene Receptor Expression by IL-4 and IFN-γ on Peripheral Immune Cells

Early

Barekzi

Negri

et al. 2007

Am J Respir Cell Mol Biol

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Arachidonic acid can be metabolized to form a group of compounds known as the cysteinyl leukotrienes (CysLT) that bind to one of two receptors to mediate their actions. On circulating cells, expression of the leukotriene receptors is low, but in inflamed tissue the receptor number is dramatically increased. We hypothesized that the cytokine milieu present during inflammation can increase receptor expression on infiltrating immune cells. Various cell populations were purified from peripheral blood and stimulated in vitro with cytokines characteristic of allergic inflammatory disorders, and CysLT receptor expression was measured using quantitative PCR analysis, Western blot, and flow cytometry. IL-4, but not IL-13, was able to significantly induce mRNA and protein levels for both CysLT receptor 1 and 2 from T cells and B cells. CysLT2 receptor expression was also significantly increased in monocytes and eosinophils after IL-4 stimulation. Surprisingly, CysLT2 receptor expression was increased in monocytes, T cells, and B cells when IFN-␥ was used as the stimulus. Factors involved in eosinophil growth and survival were tested for their ability to alter CysLT receptor expression. These results support the concept that cytokines increase expression of both receptors on lymphocytes and granulocytes, allowing these cells to be more responsive to secreted leukotrienes at sites of inflammation.Keywords: cysteinyl leukotriene receptor; T cell; B cell; eosinophil; cytokine In 1937, the slow-reacting substance of anaphylaxis was described based on the identification of a mediator derived from activated mast cells that, in an antihistamine-resistant fashion, mediated the sustained, prolonged contraction of smooth muscle. This mediator was later identified as a group of compounds known as the cysteinyl leukotrienes (CysLTs). Leukotrienes (LTs) are derived from the metabolism of arachidonic acid. Membrane phospholipids are converted into arachidonic acid by the action of a family of enzymes termed phospholipase A 2 . With cell activation, the enzyme 5-lipoxygenase (5-LO) translocates from the cytosol to the inner nuclear membrane, where in association with 5-lipoxygenase-activating protein (FLAP), it oxygenates and then dehydrates arachidonic acid to generate LTA 4 (1). LTA 4 can be conjugated with the tripeptide glutathione into the cysteinyl leukotriene LTC 4 by the enzyme LTC 4 synthase (LTC 4 S) (or the related enzyme microsomal glutathione (Received in original form July 12, 2006 and in final form January 29, 2007 ) This study was supported by a medical school grant from Merck and Co., PO1 AI50989, AI057438, and AI47737.Correspondence and requests for reprints should be addressed to John W. Steinke, Asthma and Allergic Disease Center, Box 801355, University of Virginia Health System, Charlottesville, VA 22908. E-mail: js3ch@virginia.edu This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org. CLINICAL RELEVANCEThese results show that the inflammatory milieu...

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Interferon-Î³ Up-regulates Expression of Cysteinyl Leukotriene Type 2 Receptors on Eosinophils in Asthmatic Patients

Cited by 44 publications

References 21 publications

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

IFN-γ Induces Cysteinyl Leukotriene Receptor 2 Expression and Enhances the Responsiveness of Human Endothelial Cells to Cysteinyl Leukotrienes

Concordant Modulation of Cysteinyl Leukotriene Receptor Expression by IL-4 and IFN-γ on Peripheral Immune Cells

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