Mellor, E. A. et al. Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: functional distinction from CysLT1R. Proc. Natl Acad. Sci. USA 100, 11589-11593

Harvard University, Cambridge, Massachusetts, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2003; 100(20):11589-93. DOI: 10.1073/pnas.2034927100
Source: PubMed


Cysteinyl leukotrienes (cysLTs) mediate vascular leakage and bronchoconstriction through the smooth muscle-associated CysLT type 1 receptor (CysLT1R), one of at least two loosely homologous cysLT-binding G protein-coupled receptors. We previously reported that CysLT1R is expressed by cultured human mast cells (hMCs), and that priming these cells with IL-4 enhances their sensitivity to calcium flux and cytokine generation in response to cys-LTs and the nucleotide ligand, uridine diphosphate (UDP), without increasing their surface expression of CysLT1R. We now report that hMCs express the type 2 receptor for cysLTs (CysLT2R) as well, and that the amount of surface CysLT2R protein increases in response to priming with IL-4. The selective function of CysLT2R was evident based on uninhibited IL-8 secretion by IL-4-primed hMCs stimulated with cys-LTs or UDP in the presence of the selective CysLT1R antagonist MK571. MK571 did inhibit IL-5 generation, calcium flux, and phosphorylation of extracellular signal-regulated kinase. IL-8 secretion was inhibited by pertussis toxin and a selective p38 kinase inhibitor, SB203580. The CysLT2 response may permit the cys-LTs and nucleotides generated in infection and tissue injury to elicit IL-8 generation by hMCs, potentially leading to neutrophilic infiltration, a characteristic of aerosol challenge-induced late-phase responses and of sudden death associated with asthma.

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Available from: Jose M Lora, May 13, 2014
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    • "Human mast cells express both CysLT 1 and CysLT 2 receptors and respond to Cys-LTs by mobilizing calcium, releasing pro-inflammatory cytokines and chemokines, and mediating proliferation (Mellor et al., 2001; Paruchuri et al., 2008) (Fig. 2). Interestingly, the responses to Cys-LTs (as well as those to IgE/antigen) on human mast cells are greatly enhanced by priming with T H 2 cytokines, particularly IL-4 (Hsieh et al., 2001; Mellor et al., 2002), an effect mediated in part by an increase in the transcription of LTC 4 synthase (LTC 4 S) (Hsieh et al., 2001) and in the cell surface expression of CysLT 2 receptor (Mellor et al., 2003). The CysLT 1 receptor is mostly responsible for the augmented mast cell responses to Cys-LTs or to IgE/antigen after IL-4 priming, although CysLT 2 and other putative Cys-LT receptors have been reported to contribute (Mellor et al., 2002; Mellor et al., 2003; Paruchuri et al., 2008). "
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    ABSTRACT: Sphingosine-1phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · May 2015 · European journal of pharmacology
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    • "They play an important role in triggering exacerbations of asthma through the elaboration of several soluble inflammatory mediators including cys-LTs, histamine, serine proteases, multiple cytokines and chemokines. MCs not only generate cys-LTs, but also express both CysLT1R and CysLT2R [20], [21] and respond to LTC4, LTD4, and LTE4 with a range of functions. We have demonstrated earlier that stimulation of human cord blood-derived MCs (hMCs) and/or LAD2 cells with LTD4 potently induces calcium flux [21], [22] and cytokine generation [22], [23], each of which requires CysLT1R based on pharmacologic antagonism by MK571. "
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    ABSTRACT: Cysteinyl leukotrienes (cys-LTs) are a group of lipid mediators that are potent bronchoconstrictors, powerful inducers of vascular leakage and potentiators of airway hyperresponsiveness. Cys-LTs play an essential role in asthma and are synthesized as well as activated in mast cells (MCs). Cys-LTs relay their effects mainly through two known GPCRs, CysLT1R and CysLT2R. Although protein kinase C (PKC) isoforms are implicated in the regulation of CysLT1R function, neither the role of PKCs in cys-LT-dependent MC inflammatory signaling nor the involvement of specific isoforms in MC function are known. Here, we show that PKC inhibition augmented LTD4 and LTE4-induced calcium influx through CysLT1R in MCs. In contrast, inhibition of PKCs suppressed c-fos expression as well MIP1β generation by cys-LTs. Interestingly, cys-LTs activated both PKCα and PKCε isoforms in MC. However, knockdown of PKCα augmented cys-LT mediated calcium flux, while knockdown of PKCε attenuated cys-LT induced c-fos expression and MIP1β generation. Taken together, these results demonstrate for the first time that cys-LT signaling downstream of CysLT1R in MCs is differentially regulated by two distinct PKCs which modulate inflammatory signals that have significant pathobiologic implications in allergic reactions and asthma pathology.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "Some experimental evidence indicates the possibility that CysLTR might exist as homodimers and/or heterodimers , on the basis of the observation of dimeric and oligomeric forms of CysLT 1 R in Western blots and the punctate appearance of the immunohistochemical signal in peripheral blood leukocytes (Figueroa et al., 2001) or U937 cells (Capra et al., 2005). In human MCs, which can express both receptor subtypes, Mellor et al. (2003) observed that under conditions in which CysLT 1 R is blocked, IL-5 generation results only from stimulation with the selective CysLT 2 R agonist BAY U9773 and not with cysteinyl LTs, leading them to speculate that this could arise from stimulation of a CysLT 1 /CysLT 2 heterodimer at a site inaccessible to interference from MK- 571. Finally, Beller et al., (2004b) postulated, on the basis of the magnitude of the attenuation in IgE-dependent , MC-mediated passive cutaneous anaphylaxis in CysLT 1 R/CysLT 2 R-null mice, that the effect observed in wild-type littermates was mediated through CysLT 1 / CysLT 2 heterodimers. "
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    ABSTRACT: The seven-transmembrane G protein-coupled receptors activated by leukotrienes are divided into two subclasses based on their ligand specificity for either leukotriene B(4) or the cysteinyl leukotrienes (LTC(4), LTD(4), and LTE(4)). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT(1) and BLT(2) receptors and CysLT(1) and CysLT(2) receptors has been established. However, recent findings have also indicated the existence of putative additional leukotriene receptor subtypes. Furthermore, other ligands interact with the leukotriene receptors. Finally, leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the leukotriene receptors as well as the therapeutic developments in this area of research.
    Full-text · Article · Sep 2011 · Pharmacological reviews
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