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      Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis

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          Abstract

          Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.

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          Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma.

          In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or depletion of T cells. As compared with the control subjects, the subjects with asthma had more BAL cells per 1000 cell that were positive for mRNA for interleukin-2 (P less than 0.05), 3 (P less than 0.01), 4 (P less than 0.001), and 5 (P less than 0.001) and GM-CSF (P less than 0.001). There was no significant difference between the two groups in the number of cells expressing mRNA for interferon gamma. In the subjects with asthma, mRNA for interleukin-4 and 5 was expressed predominantly by T lymphocytes. Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
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            Asthma

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              Characterization of the human cysteinyl leukotriene CysLT1 receptor.

              The cysteinyl leukotrienes-leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)-are important mediators of human bronchial asthma. Pharmacological studies have determined that cysteinyl leukotrienes activate at least two receptors, designated CysLT1 and CysLT2. The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome.
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                Author and article information

                Journal
                Clin Exp Allergy
                cea
                Clinical and Experimental Allergy
                Blackwell Publishing Ltd
                0954-7894
                1365-2222
                01 June 2006
                : 36
                : 6
                : 689-703
                Affiliations
                [* ]University of Michigan Ann Arbor, MI, USA
                []Merck & Co., Inc. West Point, PA, USA
                []Johns Hopkins University Baltimore, MD, USA
                Author notes
                Correspondence: Alkis Togias, Divisions of Allergy and Clinical Immunology and Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224-6801, USA. E-mail: atogias@ 123456jhmi.edu

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Article
                10.1111/j.1365-2222.2006.02498.x
                1569601
                16776669
                16cd74f0-1e77-4dc0-b618-eefef14754d2
                © 2006 Merck & Co., Inc. Journal compilation 2006 Blackwell Publishing Ltd
                History
                : 03 May 2005
                : 23 December 2005
                : 27 January 2006
                Categories
                Review

                Immunology
                cyslt1 receptor,leukotriene c4 synthase,allergic rhinitis,inflammation,cysteinyl leukotrienes,eosinophils,5-lipoxygenase

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