Journal articles: 'CysLT2'

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Bandeira-Melo, Christianne, Lesley J. Woods, Mojabeng Phoofolo, and Peter F. Weller. "Intracrine Cysteinyl Leukotriene Receptor–mediated Signaling of Eosinophil Vesicular Transport–mediated Interleukin-4 Secretion." Journal of Experimental Medicine 196, no. 6 (September 16, 2002): 841–50. http://dx.doi.org/10.1084/jem.20020516.

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We investigated whether cysteinyl leukotrienes (cysLT) are intracrine signal transducers that regulate human eosinophil degranulation mechanisms. Interleukin (IL)-16, eotaxin, and RANTES stimulate vesicular transport–mediated release of preformed, granule-derived IL-4 and RANTES from eosinophils and the synthesis at intracellular lipid bodies of LTC4, the dominant 5-lipoxygenase–derived eicosanoid in eosinophils. 5-Lipoxygenase inhibitors blocked IL-16–, eotaxin-, and RANTES-induced IL-4 release; but neither exogenous LTC4, LTD4, nor LTE4 elicited IL-4 release. Only after membrane permeabilization enabled cysLTs to enter eosinophils did LTC4 and LTD4 stimulate IL-4, but not RANTES, release. LTC4-elicited IL-4 release was pertussis toxin inhibitable, but inhibitors of the two known G protein–coupled cysLT receptors (cysLTRs) (CysLT1 and CysLT2) did not block LTC4-elicited IL-4 release. LTC4 was 10-fold more potent than LTD4 and at low concentrations (0.3–3 nM) elicited, and at higher concentrations (>3 nM) inhibited, IL-4 release from permeabilized eosinophils. Likewise with intact eosinophils, LTC4 export inhibitors, which increased intracellular LTC4, inhibited eotaxin-elicited IL-4 release. Thus, LTC4 acts, via an intracellular cysLTR distinct from CysLT1 or CysLT2, as a signal transducer to selectively regulate IL-4 release. These results demonstrate that LTC4, well recognized as a paracrine mediator, may also dynamically govern inflammatory and immune responses as an intracrine mediator of eosinophil cytokine secretion.

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Jiang, Yongfeng, Laura A. Borrelli, Yoshihide Kanaoka, Brian J. Bacskai, and Joshua A. Boyce. "CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene–dependent mitogenic responses of mast cells." Blood 110, no. 9 (November 1, 2007): 3263–70. http://dx.doi.org/10.1182/blood-2007-07-100453.

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Abstract Cysteinyl leukotrienes (cys-LTs) induce inflammation through 2 G protein–coupled receptors (GPCRs), CysLT1 and CysLT2, which are coexpressed by most myeloid cells. Cys-LTs induce proliferation of mast cells (MCs), transactivate c-Kit, and phosphorylate extracellular signal-regulated kinase (ERK). Although MCs express CysLT2, their responses to cys-LTs are blocked by antagonists of CysLT1. We demonstrate that CysLT2 interacts with CysLT1, and that knockdown of CysLT2 increases CysLT1 surface expression and CysLT1-dependent proliferation of cord blood–derived human MCs (hMCs). Cys-LT–mediated responses were absent in MCs from mice lacking CysLT1 receptors, but enhanced by the absence of CysLT2 receptors. CysLT1 and CysLT2 receptors colocalized to the plasma membranes and nuclei of a human MC line, LAD2. Antibody-based fluorescent lifetime imaging microscopy confirmed complexes containing both receptors based on fluorescence energy transfer. Negative regulation of CysLT1-induced mitogenic signaling responses of MCs by CysLT2 demonstrates physiologically relevant functions for GPCR heterodimers on primary cells central to inflammation.

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Drost, Adriana, Mirjam Funk, Karoline Norz, Anne Zipfel, Lothar Kanz, and Robert Mohle. "Cysteinyl Leukotrienes Signal Via Overexpressed CysLT1, but Not CysLT2 Receptor In Chronic Lymphocytic Leukemia." Blood 116, no. 21 (November 19, 2010): 3612. http://dx.doi.org/10.1182/blood.v116.21.3612.3612.

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Abstract Abstract 3612 The G Protein-coupled receptors (GPCRs) CysLT1 and CysLT2 are both expressed in peripheral blood mononuclear cells (PBMNC). Their ligands are inflammatory mediators of the cysteinyl leukotriene (cysLT) family and contribute, together with ligands of other GPCRs such as chemokines, to migration and proliferation of a variety of cell types. In the present study, we demonstrate by real-time RT-PCR that CysLT1 mRNA is overexpressed in B-CLL cells compared to both normal PBMNC and normal CD19+ B cells, whereas only low levels of CysLT2 mRNA are present. GPCR-typical cellular responses such as intracellular calcium fluxes and actin polymerization, which were induced by the cysLT LTD4 in CLL cells in a dose-dependent manner, were suppressed by the CysLT1 antagonist MK571, the prototype of the lukast family of drugs used in asthma treatment (e.g., montelukast). However, MK571 and other lukasts also block the leukotriene transporter MRP. The fact that the CysLT1 antagonist LY171883, which has no effect on MRP, also abrogated the responses of CLL cells indicates that the effects of cysLTs are mediated solely by CysLT1. Moreover, also chemotaxis was induced by the cysLT LTD4 in B-CLL cells (optimum at low nanomolar concentrations) and could be blocked by MK571. We further observed inhibiting effects of MK571 on cysLT-induced Erk/MAP kinase phosphorylation in B-CLL cells, which suggests an involvement of CysLT1 in cell proliferation. Indeed, MK571 significantly induced apoptosis of CLL cells in vitro and reduced survival of cultured B-CLL cells. However, the concentrations for a significant reduction of cell viability were higher (1-10 μM) than the concentration required for efficient CysLT1 receptor inhibition (0.1 μM). Thus, the influence of MK571 on B-CLL cell survival may mainly be due to direct effects on apoptosis occuring at the higher dose level and/or blocking of the leukotriene transporter MRP. Accordingly, LY171883 and the combined CysLT1/2 antagonist Bay-u9773 did not induce CLL apoptosis. Our results suggest that CysLT1 is overexpressed in B-CLL cells and involved in cell trafficking, similar to the chemokine receptor CXCR4. Considering the redundancy among GPCRs and the limited effect of MK571 on cell survival, CysLT1 for its own represents a less attractive therapeutic target using the currently available CysLT1 antagonists of the lukast family. However, combined inhibition of several GPCRs highly expressed in CLL cells including cysLT1 and CXCR4 may constitute a promising therapeutic approach and should be further evaluated. Disclosures: No relevant conflicts of interest to declare.

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Ballerini, P., P. Di Iorio, R. Ciccarelli, F. Caciagli, A. Polp, A. Beraudi, S. Buccella, et al. "P2Y1 and Cysteinyl Leukotriene Receptors Mediate Purine and Cysteinyl Leukotriene Co-Release in Primary Cultures of Rat Microglia." International Journal of Immunopathology and Pharmacology 18, no. 2 (April 2005): 255–68. http://dx.doi.org/10.1177/039463200501800208.

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Inflammation is widely recognized as contributing to the pathology of acute and chronic neurodegenerative conditions. Microglial cells are pathologic sensors in the brain and activated microglia have been viewed as detrimental. Leukotriene, including cysteinyl leukotrienes (CysLTs) are suggested to be involved in brain inflammation and neurological diseases and ATP, by its receptors is a candidate for microglia activation. A23187 (10μM) stimulated microglia to co-release CysLTs and [3H]adenine based purines ([3H]ABPs), mainly ATP. The biosynthetic production of CysLTs was abolished by 10μM MK-886, an inhibitor of 5-lipoxygenase-activating protein activity. RT-PCR analysis showed that microglia expressed both CysLT1 / CysLT2 receptors, P2Y1 ATP-receptors and several members of the ATP binding cassette (ABC) transporters including MRP1, MRP4 and Pgp. The increase in [Ca2+]i elicited by LTD4 (0.1 μM) and 2MeSATP (100μM), agonists for CysLT- and P2Y1-receptors, was abolished by the respective antagonists, BAYu9773 (0.5 μM) and suramin (50 μM). The stimulation of both receptor subtypes, induced a concomitant increase in the release of both [3H]ABPs and CysLTs that was blocked by the antagonists and significantly reduced by a cocktail of ABC transporter inhibitors, BAPTA/AM (intracellular Ca2+ chelator) and staurosporine (0.1 μM, PKC blocker). P2Y antagonist was unable to antagonise the effects of LTD4 and BAYu9773 did not reduce the effects of 2MeSATP. These data suggest that: i) the efflux of purines and cysteinyl-leukotrienes is specifically and independently controlled by the two receptor types, ii) calcium, PKC and the ABC transporter system can reasonably be considered common mechanisms underlying the release of ABPs and CysLTs from microglia. The blockade of P2Y1 or CysLT1/CysLT2 receptors by specific antagonists that abolished the raise in [Ca2+]i and drastically reduced the concomitant efflux of both compounds, as well as the effects of BAPTA and staurosporine support this hypothesis. In conclusion, the data of the present study suggest a cross talk between the purine and leukotriene systems in a possible autocrine/paracrine control of the microglia-mediated initiation and progression of an inflammatory response.

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Sasaki, Fumiyuki, and Takehiko Yokomizo. "The leukotriene receptors as therapeutic targets of inflammatory diseases." International Immunology 31, no. 9 (May 28, 2019): 607–15. http://dx.doi.org/10.1093/intimm/dxz044.

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Abstract Leukotrienes (LTs) are inflammatory mediators derived from arachidonic acid. LTs include the di-hydroxy acid LT (LTB4) and the cysteinyl LTs (CysLTs; LTC4, LTD4 and LTE4), all of which are involved in both acute and chronic inflammation. We and other groups identified a high-affinity LTB4 receptor, BLT1; the LTC4 and LTD4 receptors, CysLT1 and CysLT2; and the LTE4 receptor, GPR99. Pharmacological studies have shown that BLT1 signaling stimulates degranulation, chemotaxis and phagocytosis of neutrophils, whereas CysLT1 and CysLT2 signaling induces airway inflammation by increasing vascular permeability and the contraction of bronchial smooth muscle. Recently, we and other groups suggested that the LTB4–BLT1 axis and the cysteinyl LTs–CysLT1/2 axis are involved in chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, atherosclerosis, arthritis, obesity, cancer and age-related macular degeneration using animal models for disease and gene knockout mice. This review describes the classical and novel functions of LTs and their receptors in several inflammatory diseases and discusses the potential clinical applications of antagonists for LT receptors and inhibitors of LT biosynthesis.

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Slater, Kayleigh, Aisling B. Heeran, Sandra Garcia-Mulero, Helen Kalirai, Rebeca Sanz-Pamplona, Arman Rahman, Nebras Al-Attar, et al. "High Cysteinyl Leukotriene Receptor 1 Expression Correlates with Poor Survival of Uveal Melanoma Patients and Cognate Antagonist Drugs Modulate the Growth, Cancer Secretome, and Metabolism of Uveal Melanoma Cells." Cancers 12, no. 10 (October 13, 2020): 2950. http://dx.doi.org/10.3390/cancers12102950.

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Metastatic uveal melanoma (UM) is a rare, but often lethal, form of ocular cancer arising from melanocytes within the uveal tract. UM has a high propensity to spread hematogenously to the liver, with up to 50% of patients developing liver metastases. Unfortunately, once liver metastasis occurs, patient prognosis is extremely poor with as few as 8% of patients surviving beyond two years. There are no standard-of-care therapies available for the treatment of metastatic UM, hence it is a clinical area of urgent unmet need. Here, the clinical relevance and therapeutic potential of cysteinyl leukotriene receptors (CysLT1 and CysLT2) in UM was evaluated. High expression of CYSLTR1 or CYSLTR2 transcripts is significantly associated with poor disease-free survival and poor overall survival in UM patients. Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21–6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67–3.17). High CysLT1 expression shows a statistically significant (p = 0.041) correlation with ciliary body involvement, a poor prognostic indicator in UM. Small molecule drugs targeting CysLT1 were vastly superior at exerting anti-cancer phenotypes in UM cell lines and zebrafish xenografts than drugs targeting CysLT2. Quininib, a selective CysLT1 antagonist, significantly inhibits survival (p < 0.0001), long-term proliferation (p < 0.0001), and oxidative phosphorylation (p < 0.001), but not glycolysis, in primary and metastatic UM cell lines. Quininib exerts opposing effects on the secretion of inflammatory markers in primary versus metastatic UM cell lines. Quininib significantly downregulated IL-2 and IL-6 in Mel285 cells (p < 0.05) but significantly upregulated IL-10, IL-1β, IL-2 (p < 0.0001), IL-13, IL-8 (p < 0.001), IL-12p70 and IL-6 (p < 0.05) in OMM2.5 cells. Finally, quininib significantly inhibits tumour growth in orthotopic zebrafish xenograft models of UM. These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.

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Voisin, Tiphaine, Caroline Perner, Marie-Angele Messou, Stephanie Shiers, Saltanat Ualiyeva, Yoshihide Kanaoka, Theodore J. Price, et al. "The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch." Proceedings of the National Academy of Sciences 118, no. 13 (March 22, 2021): e2022087118. http://dx.doi.org/10.1073/pnas.2022087118.

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Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2−/− mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.

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Nettis, Eustachio, Maddalena D'Erasmo, Elisabetta Di Leo, Gianfranco Calogiuri, Vincenzo Montinaro, Antonio Ferrannini, and Angelo Vacca. "The Employment of Leukotriene Antagonists in Cutaneous Diseases Belonging to Allergological Field." Mediators of Inflammation 2010 (2010): 1–6. http://dx.doi.org/10.1155/2010/628171.

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Leukotrienes (LTs) are potent biological proinflammatory mediators. LTC4, LTD4, and LTE4 are more frequently involved in chronic inflammatory responses and exert their actions binding to a cysteinyl-LT 1 (CysLT1) receptor and a cysteinyl-LT 2 (CysLT2) receptor. LTs receptor antagonists available for clinical use demonstrate high-affinity binding to the CysLT1 receptor. In this paper the employment of anti-LTs in allergic cutaneous diseases is analyzed showing that several studies have recently reported a beneficial effects of these agents (montelukast and zafirlukast as well as zileuton) for the treatment of some allergic cutaneous related diseases-like chronic urticaria and atopic eczema although their proper application remains to be established.

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Sjoberg, Jan, Frida Schain, Ylva Tryselius, Linda Backman, Anna Porwit, Cheng Liu, Dawei Xu, et al. "Novel Findings Support a Patophysiological Role of the Arachidonic Cascade in Hodgkin Lymphoma." Blood 110, no. 11 (November 16, 2007): 2269. http://dx.doi.org/10.1182/blood.v110.11.2269.2269.

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Abstract Lipoxygenases (LO) are a family of structurally related enzymes which catalyze the conversion of the fatty acid arachidonic acid to biologically active metabolites. The key enzyme in leukotriene synthesis, 5- LO, catalyzes the first step in the metabolism of arachidonic acid to leukotriene (LT) C4. This compound and its metabolites LTD4 and LTE4, collectively called cysteinyl leukotrienes (cysLT), can bind to two high-affinity receptors, named cysLT1 and cysLT2. A sister enzyme to 5-LO is 15-LO-1 which also can catalyze the formation of bioactive metabolites. Arachidonic acid metabolites have traditionally been linked to inflammation and asthma but several studies also indicate a role of these metabolites in carcinogenesis In our studies of arachidonic acid metabolism in human lymphomas, we have identified the expression of 15-LO-1 and receptors for cysLT in primary as well as cultured Hodgkin-Reed Sternberg (H-RS) cells. In tumor tissue, H-RS cells positive for 15-LO-1 and the cysLT1 receptor were detected immunohistochemically in 13/15 and 12/16 cases, respectively. The presence of mRNA for 15-LO-1 and the cysLT1 and 2 receptors was confirmed by microarray analysis of laser dissected H-RS cells. Studies of 15-LO-1 gene transcription revealed that STAT6 activation and chromatin remodeling by DNA demethylation and histone acetylation are crucial for transcriptional activation of this gene in cultured H-RS cells. Incubation of the Hodgkin lymphoma-derived cell lines KMH2 and L1236 with LTD4 led to a robust calcium response that was completely abolished in presence of the cysLT1 receptor inhibitor zafirlukast. In L1236 cells, LTD4 induced increased DNA synthesis, interleukin-13 transcription and release of TNF-alpha, interleukin-6 and interleukin-8 in a dose-dependent manner, all of which were inhibited by zafirlukast. Thus, as the H-RS cells lack the expression of 5-LO, we hypothesize that that tumor-associated cysLT-producing inflammatory cells, such as eosinophils and mast cells, contribute to the pathogenesis of Hodgkin lymphoma through induction of tumor cell proliferation and cytokine release. Furthermore, immunohistochemical studies of 20 non-Hodgkin lymphomas revealed the expression of cysLT1 receptors also in primary mediastinal B cell lymphomas (PMBCL), and the functionality of these receptors was confirmed in the PMBCL-derived cell line MedB1. Taken together, these novel findings support a role for arachidonic acid metabolites in the pathogenesis of lymphoma.

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Sekioka, Tomohiko, Michiaki Kadode, Noriko Osakada, Manabu Fujita, Naoya Matsumura, Yoshiyuki Yamaura, Shinji Nakade, Takeshi Nabe, and Kazuhito Kawabata. "A new CysLT1 and CysLT2 receptors-mediated anaphylaxis guinea pig model." Prostaglandins, Leukotrienes and Essential Fatty Acids 119 (April 2017): 18–24. http://dx.doi.org/10.1016/j.plefa.2017.03.002.

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Ouyang, Yuhui, Atsushi Kamijo, Shin-ichi Murata, Atsushi Okamoto, Shuichiro Endo, Ryohei Katoh, and Keisuke Masuyama. "Expression of cysLT1 and cysLT2 Receptor in Chronic Hyperplastic Eosinophilic Sinusitis." ACTA HISTOCHEMICA ET CYTOCHEMICA 42, no. 6 (2009): 191–96. http://dx.doi.org/10.1267/ahc.09031.

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Boyce, J. A., and Y. Jiang. "CysLT2 Receptors Negatively Regulate CysLT1 Receptor Functions on Mast Cells Through Heterodimerization." Journal of Allergy and Clinical Immunology 119, no. 1 (January 2007): S314. http://dx.doi.org/10.1016/j.jaci.2006.12.599.

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Steinke, John W., Spencer C. Payne, and Larry Borish. "Interleukin-4 in the Generation of the AERD Phenotype: Implications for Molecular Mechanisms Driving Therapeutic Benefit of Aspirin Desensitization." Journal of Allergy 2012 (January 3, 2012): 1–9. http://dx.doi.org/10.1155/2012/182090.

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Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase (LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and the hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa and nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S by mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished expression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase 1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype of AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization provides therapeutic benefit for AERD patients.

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Jiang, Y., and J. Boyce. "CysLT1 and CysLT2 Receptors Form Functional Heterodimers on Human Mast Cells and Neutrophils." Journal of Allergy and Clinical Immunology 117, no. 2 (February 2006): S68. http://dx.doi.org/10.1016/j.jaci.2005.12.273.

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Itadani, Satoshi, Shinya Takahashi, Masaki Ima, Tetsuya Sekiguchi, Yoshiyuki Aratani, Hiromu Egashira, Naoya Matsumura, et al. "Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid." Bioorganic & Medicinal Chemistry 23, no. 9 (May 2015): 2079–97. http://dx.doi.org/10.1016/j.bmc.2015.03.011.

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ROELOFS, K. "Activation of monocytes by cysteinyl leukotrienes (CysLT) in a CysLT2 receptor-dependent fashion*1." Journal of Allergy and Clinical Immunology 113, no. 2 (February 2004): S248. http://dx.doi.org/10.1016/j.jaci.2004.01.357.

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Hui, Yiqun, Guochang Yang, Helen Galczenski, David J. Figueroa, Christopher P. Austin, Neal G. Copeland, Debra J. Gilbert, Nancy A. Jenkins, and Colin D. Funk. "The Murine Cysteinyl Leukotriene 2 (CysLT2) Receptor." Journal of Biological Chemistry 276, no. 50 (October 8, 2001): 47489–95. http://dx.doi.org/10.1074/jbc.m107556200.

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Two classes of cysteinyl leukotriene receptor, CysLT1and CysLT2, have been identified and pharmacologically characterized in human tissues. Although the CysLT1receptor mediates the proinflammatory effects of leukotrienes in human asthma, the physiological roles of CysLT2receptor are not defined, and a suitable mouse model would be useful in delineating function. We report here the molecular cloning and characterization of the mouse CysLT2receptor (mCysLT2R) from heart tissue. mCysLT2R cDNA encodes a protein of 309 amino acids, truncated at both ends compared with the human ortholog (hCysLT2R). The gene resides on the central region of mouse chromosome 14 and is composed of 6 exons with the entire coding region located in the last exon. Two 5′-untranslated region splice variants were identified with the short form lacking exon 3 as the predominant transcript. Although the overall expression of mCysLT2R is very low, the highest expression was detected in spleen, thymus, and adrenal gland by ribonuclease protection assay, and discrete sites of expression in heart were observed byin situhybridization. Intracellular calcium mobilization in response to cysteinyl leukotriene administration was detected in human embryonic kidney 293T cells transfected with recombinant mCysLT2R with a rank order of potency leukotriene C4(LTC4) = LTD4≫ LTE4. [3H]LTD4binding to membranes expressing mCysLT2R could be effectively competed by LTC4and LTD4and only partially inhibited by LTE4and BAYu9773. The identification of mCysLT2R will be useful for establishing CysLT2R-deficient mice and determining novel leukotriene functions.

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Sheng, Wen-Wen, Cheng-Tan Li, Wei-Ping Zhang, Yu-Mei Yuan, Hua Hu, San-Hua Fang, Lei Zhang, and Er-Qing Wei. "Distinct roles of CysLT1 and CysLT2 receptors in oxygen glucose deprivation-induced PC12 cell death." Biochemical and Biophysical Research Communications 346, no. 1 (July 2006): 19–25. http://dx.doi.org/10.1016/j.bbrc.2006.05.023.

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Di Gennaro, Antonio, Ana Carolina Araújo, Albert Busch, Hong Jin, Dick Wågsäter, Emina Vorkapic, Kenneth Caidahl, et al. "Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm." Proceedings of the National Academy of Sciences 115, no. 8 (February 5, 2018): 1907–12. http://dx.doi.org/10.1073/pnas.1717906115.

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Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1α (MIP-1α) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.

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Bautz, Frank, Claudio Denzlinger, Lothar Kanz, and Robert Möhle. "Chemotaxis and transendothelial migration of CD34+hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1." Blood 97, no. 11 (June 1, 2001): 3433–40. http://dx.doi.org/10.1182/blood.v97.11.3433.

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Recent studies suggest that bone marrow (BM)–derived chemotactic mediators such as chemokines play key roles in hematopoietic stem cell trafficking. Lipid mediators, particularly leukotrienes, are involved in leukocyte chemotaxis during inflammation but have also been detected in the normal BM. Therefore, the effects of leukotrienes on hematopoietic progenitor cells were analyzed. Cysteinyl leukotrienes, particularly leukotriene D4 (LTD4), induced strong intracellular calcium fluxes and actin polymerization in mobilized and BM CD34+ progenitors. Chemotaxis and in vitro transendothelial migration of CD34+ and more primitive CD34+/CD38− cells were 2-fold increased by LTD4 at an optimum concentration of 25 to 50 nM. Accordingly, CD34+ cells expressed the 7-transmembrane LTD4 receptor CysLT1 by reverse transcriptase–polymerase chain reaction and Western blot. Effects of LTD4 were suppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin. In contrast, LTB4 induced strong responses only in mature granulocytes. LTD4-induced calcium fluxes were also observed in granulocytes but were not reduced by MK-571, suggesting that these effects were mediated by other receptors (eg, CysLT2) rather than by CysLT1. In addition, expression of 5-lipoxygenase, the key enzyme of leukotriene biosynthesis, was detected in both hematopoietic progenitor cells and mature leukocytes. The study concludes that the functionally active LTD4 receptor CysLT1 is preferentially expressed in immature hematopoietic progenitor cells. LTD4 released in the BM might regulate progenitor cell trafficking and could also act as an autocrine mediator of hematopoiesis. This would be a first physiologic effect of cysteinyl leukotrienes apart from the many known pathophysiologic actions related to allergy and inflammation.

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Huang, Shih-Che. "Leukotriene-induced contraction is mediated by cysteinyl leukotriene receptor CysLT1 in guinea pig fundus but by CysLT1 and CysLT2 in antrum." Life Sciences 88, no. 17-18 (April 2011): 819–24. http://dx.doi.org/10.1016/j.lfs.2011.02.023.

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Itadani, Satoshi, Kentaro Yashiro, Yoshiyuki Aratani, Tetsuya Sekiguchi, Atsushi Kinoshita, Hideki Moriguchi, Nobukazu Ohta, et al. "Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma." Journal of Medicinal Chemistry 58, no. 15 (July 22, 2015): 6093–113. http://dx.doi.org/10.1021/acs.jmedchem.5b00741.

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Corrigan, Chris, Kirsty Mallett, Sun Ying, David Roberts, Abhi Parikh, Glenis Scadding, and Tak Lee. "Expression of the cysteinyl leukotriene receptors cysLT1 and cysLT2 in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis." Journal of Allergy and Clinical Immunology 115, no. 2 (February 2005): 316–22. http://dx.doi.org/10.1016/j.jaci.2004.10.051.

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Różańska, Małgorzata, Paweł Bielecki, Joanna Reszeć, Krzysztof Kowal, and Marek Rogowski. "Cysteinyl leukotriene 1 receptor expression in nasal polyps." Otolaryngologia Polska 72, no. 5 (October 1, 2018): 1–5. http://dx.doi.org/10.5604/01.3001.0012.5422.

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Cysteinyl leukotrienes (CysLTs) have been implicated in the pathogenesis of chronic rhinosinusitis (CRS). This study was undertaken to better understand the role of CysLTs in the development of CRS through 1). assessment of the pattern of expression of CysLT1 receptor in nasal polyps from patients with CRS and 2). correlation of expression of CysLT1 receptor with clinical features. Expression of CysLT1 receptor was evaluated immunohistochemically in nasal polyps from 20 patients with CRS and nasal mucosa from 10 control subject undergoing plastic surgery of the nose. Patients with CRS showed significantly higher expression of CysLT1 receptor as compared with the control group (p<0.05). The expression of CysLT1 receptor in sub-epithelial inflammatory infiltrates tended to be higher in patients with CRS and allergy as compared with patients with CRS but without allergy (p=0.07). In particular, the expression of CysLT1 receptor in sub-epithelial inflammatory infiltrates was significantly greater in 3 patients with CRS and drug allergy as compared with patients with CRS but without drug allergy (p=0.03). Increased expression of CysLT1 receptor in inflamed mucosa of nasal polyps in patients with allergy might suggest particular role of CysLTs in the pathogenesis of nasal polyps in this group of patients.

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Colazzo, Francesca, Paolo Gelosa, Elena Tremoli, Luigi Sironi, and Laura Castiglioni. "Role of the Cysteinyl Leukotrienes in the Pathogenesis and Progression of Cardiovascular Diseases." Mediators of Inflammation 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/2432958.

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Cysteinyl leukotrienes (CysLTs) are potent lipid inflammatory mediators synthesized from arachidonic acid, through the 5-lipoxygenase (5-LO) pathway. Owing to their properties, CysLTs play a crucial role in the pathogenesis of inflammation; therefore, CysLT modifiers as synthesis inhibitors or receptor antagonists, central in asthma management, may become a potential target for the treatment of other inflammatory diseases such as the cardiovascular disorders. 5-LO pathway activation and increased expression of its mediators and receptors are found in cardiovascular diseases. Moreover, the cardioprotective effects observed by using CysLT modifiers are promising and contribute to elucidate the link between CysLTs and cardiovascular disease. The aim of this review is to summarize the state of present research about the role of the CysLTs in the pathogenesis and progression of atherosclerosis and myocardial infarction.

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Duah, Ernest, Lakshminarayan Reddy Teegala, Vinay Kondeti, Ravi K. Adapala, Venkateshwar G. Keshamouni, Yoshihide Kanaoka, K. Frank Austen, Charles K. Thodeti, and Sailaja Paruchuri. "Cysteinyl leukotriene 2 receptor promotes endothelial permeability, tumor angiogenesis, and metastasis." Proceedings of the National Academy of Sciences 116, no. 1 (December 17, 2018): 199–204. http://dx.doi.org/10.1073/pnas.1817325115.

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Cysteinyl leukotrienes (cys-LTs) are proinflammatory mediators that enhance vascular permeability through distinct receptors (CysLTRs). We found that CysLT2R regulates angiogenesis in isolated mouse endothelial cells (ECs) and in Matrigel implants in WT mice and enhances EC contraction and permeability via the Rho-dependent myosin light chain 2 and vascular endothelial (VE)-cadherin axis. Since solid tumors utilize aberrant angiogenesis for their growth and metastasis and their vessels exhibit vascular hyperpermeability, we hypothesized that CysLT2R, via its actions on the endothelium, might regulate tumor growth. Both tumor growth and metastases of adoptively transferred syngeneic Lewis lung carcinoma (LLC) cells are significantly reduced in CysLT2R-null mice (Cysltr2−/−) compared with WT and CysLT1R-null mice (Cysltr1−/−). In WT recipients of LLC cells, CysLT2R expression is significantly increased in the tumor vasculature, compared with CysLT1R. Further, the tumor vasculature in Cysltr2−/− recipients exhibited significantly improved integrity, as revealed by increased pericyte coverage and decreased leakage of i.v.-administered Texas Red-conjugated dextran. Administration of a selective CysLT2R antagonist significantly reduced LLC tumor volume, vessel density, dextran leakage, and metastases in WT mice, highlighting CysLT2R as a VEGF-independent regulator of the vasculature promoting risk of metastasis. Thus, both genetic and pharmacological findings establish CysLT2R as a gateway for angiogenesis and EC dysregulation in vitro and ex vivo and in an in vivo model with a mouse tumor. Our data suggest CysLT2R as a possible target for intervention.

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Sadybekov, Arman A., Rebecca L. Brouillette, Egor Marin, Anastasiia V. Sadybekov, Aleksandra Luginina, Anastasiia Gusach, Alexey Mishin, et al. "Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR." Biomolecules 10, no. 12 (December 3, 2020): 1634. http://dx.doi.org/10.3390/biom10121634.

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Cysteinyl leukotriene G protein-coupled receptors, CysLT1R and CysLT2R, regulate bronchoconstrictive and pro-inflammatory effects and play a key role in allergic disorders, cardiovascular diseases, and cancer. CysLT1R antagonists have been widely used to treat asthma disorders, while CysLT2R is a potential target against uveal melanoma. However, very few selective antagonist chemotypes for CysLT receptors are available, and the design of such ligands has proved to be challenging. To overcome this obstacle, we took advantage of recently solved crystal structures of CysLT receptors and an ultra-large Enamine REAL library, representing a chemical space of 680 M readily available compounds. Virtual ligand screening employed 4D docking models comprising crystal structures of CysLT1R and CysLT2R and their corresponding ligand-optimized models. Functional assessment of the candidate hits yielded discovery of five novel antagonist chemotypes with sub-micromolar potencies and the best Ki = 220 nM at CysLT1R. One of the hits showed inverse agonism at the L129Q constitutively active mutant of CysLT2R, with potential utility against uveal melanoma.

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Hideaki, Shirasaki, Etsuko Kanaizumi, Manabu Fujita, and Tetsuo Himi. "134 Expression and Localization of CYSLT2 Receptor in Human Nasal Mucosa." World Allergy Organization Journal 5 (February 2012): S44—S45. http://dx.doi.org/10.1097/01.wox.0000411879.06407.f8.

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Sjoberg, Jan, Frida Schain, Ylva Tryselius, Linda Backman, Maria Malec, Anna Porwit-MacDonald, Magnus Bjorkholm, and Hans-Erik Claesson. "Leukotrienes Stimulate the Release of Cytokines and Proliferation of Hodgkin Reed-Sternberg Cells." Blood 108, no. 11 (November 1, 2006): 2263. http://dx.doi.org/10.1182/blood.v108.11.2263.2263.

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Abstract Background: Classical Hodgkin Lymphoma (cHL) is characterized by a minority of malignant cells, the so-called Hodgkin- and Reed Sternberg (H-RS) cells, surrounded by inflammatory cells such as eosinophils, macrophages and mast cells. In contrast to other tumors, the malignant H-RS cells constitute only a few percent of the total cells in the affected tissue. Therefore, it is generally believed that various compounds released by H-RS cells and the interaction between H-RS cells and by- stander cells are of great importance in the pathophysiology of cHL disease. Aim: To characterize the expression and function of cysteinyl leukotriene receptors (CysLTR) in cHL. Methods and results: We have identified functional CysLT1R in a HL cell line as shown by increased intracellular calcium release upon leukotriene (LT) D4 stimulation (100–500 nM). This response was completely blocked after addition of zafirlukast, a specific CysLT1R antagonist. Immunohistochemical studies of paraffin embedded cHL tissue showed H-RS cells positive for CysLT1R in 12 of 16 cHL tumors. Microarray analysis of laser captured H-RS cells from 3 tumors not only confirmed the expression of CysLT1R transcripts, but also showed expression of the CysLT2R gene (P. Murray, personal communication). The possible role of the CysLT2R in H-RS cells will be discussed. The HL cell line was cultured in the presence of LTD4 (100 nM) to investigate the effects of CysLT signaling in H-RS cells. Real-time RT-PCR analysis showed up-regulation of TNF-α, interleukin (IL)-6, IL-8 and IL-13 mRNA after stimulation with LTD4. Furthermore, the effects of LTD4 on cytokine protein secretion by the HL cells were studied by flow cytometry. The results showed a markedly increased secretion of TNF-α, IL-6 and IL-8 upon LTD4 stimulation. In addition, LTD4 stimulated cell proliferation in a dose-dependent manner. Conclusion: Since H-RS cells are surrounded by CysLT producing cells (eosinophils, macrophages and mast cells), these results indicate that CysLT signaling could be of importance in the pathogenesis of cHL by contributing to proliferation of the tumor cell population and the disturbed cytokine features of this tumor. This study was supported by the Swedish Cancer Society.

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Liu, Tao, Junrui Lin, Chunli Feng, Nora Barrett, Tanya Laidlaw, and Joshua Boyce. "Leukotriene D4 antagonizes CysLT2 receptor signaling and LTC4-driven immunopathology in vivo." Journal of Allergy and Clinical Immunology 145, no. 2 (February 2020): AB90. http://dx.doi.org/10.1016/j.jaci.2019.12.054.

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Yoshioka, Masakata, Hironori Sagara, Fumiyuki Takahashi, Norihiro Harada, Kazuto Nishio, Akio Mori, Hiroko Ushio, et al. "Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 296, no. 1 (January 2009): L30—L36. http://dx.doi.org/10.1152/ajplung.00026.2008.

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Multidrug resistance-associated protein 1 (MRP1) is a cysteinyl leukotriene (CysLT) export pump expressed on mast cells. CysLTs are crucial mediators in allergic airway disease. However, biological significance of MRP1 in allergic airway inflammation has not yet been elucidated. In this study, we sensitized wild-type control mice ( mrp1+/+) and MRP1-deficient mice ( mrp1−/−) to ovalbumin (OVA) and challenged them with OVA by aerosol. Airway inflammation and goblet cell hyperplasia after OVA exposure were reduced in mrp1−/− mice compared with mrp1+/+ mice. Furthermore, CysLT levels in bronchoalveolar lavage fluid (BALF) from OVA-exposed mrp1−/− mice were significantly lower than those from OVA-exposed mrp1+/+ mice. Levels of OVA-specific IgE, IL-4, and IL-13 in BALF were also decreased in OVA-exposed mrp1−/− mice. IgE-mediated release of CysLTs from murine bone marrow-derived mast cells was markedly impaired by MRP1 deficiency. Our results indicate that MRP1 plays an important role in the development of allergic airway inflammation through regulation of IgE-mediated CysLT export from mast cells.

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Takasaki, Jun, Masazumi Kamohara, Mitsuyuki Matsumoto, Tetsu Saito, Toru Sugimoto, Takahide Ohishi, Hiroyuki Ishii, et al. "The Molecular Characterization and Tissue Distribution of the Human Cysteinyl Leukotriene CysLT2 Receptor." Biochemical and Biophysical Research Communications 274, no. 2 (August 2000): 316–22. http://dx.doi.org/10.1006/bbrc.2000.3140.

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Wang, Meng-Ling, Xiao-Jia Huang, San-Hua Fang, Yu-Mei Yuan, Wei-Ping Zhang, Yu-Bi Lu, Qian Ding, and Er-Qing Wei. "Leukotriene D4 induces brain edema and enhances CysLT2 receptor-mediated aquaporin 4 expression." Biochemical and Biophysical Research Communications 350, no. 2 (November 2006): 399–404. http://dx.doi.org/10.1016/j.bbrc.2006.09.057.

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Sekioka, Tomohiko, Michiaki Kadode, Masanori Fujii, Kazuhito Kawabata, Takashi Abe, Michiaki Horiba, Shigekatsu Kohno, and Takeshi Nabe. "Expression of CysLT2 receptors in asthma lung, and their possible role in bronchoconstriction." Allergology International 64, no. 4 (October 2015): 351–58. http://dx.doi.org/10.1016/j.alit.2015.04.008.

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Baptista-dos-Reis, Renata, Valdirene S. Muniz, and Josiane S. Neves. "Multifaceted Roles of Cysteinyl Leukotrienes in Eliciting Eosinophil Granule Protein Secretion." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/848762.

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Cysteinyl leukotrienes (cysLTs) are cell membrane-impermeant lipid mediators that play major roles in the pathogenesis of eosinophilic inflammation and are recognized to act via at least 2 receptors, namely, cysLT1receptor (cysLT1R) and cysLT2receptor (cysLT2R). Eosinophils, which are granulocytes classically associated with host defense against parasitic helminthes and allergic conditions, are distinguished from leukocytes by their dominant population of cytoplasmic crystalloid (also termed secretory, specific, or secondary) granules that contain robust stores of diverse preformed proteins. Human eosinophils are the main source of cysLTs and are recognized to express both cysLTs receptors (cysLTRs) on their surface, at the plasma membrane. More recently, we identified the expression of cysLTRs in eosinophil granule membranes and demonstrated that cysLTs, acting via their granule membrane-expressed receptors, elicit secretion from cell-free human eosinophil granules. Herein, we review the multifaceted roles of cysLTs in eliciting eosinophil granule protein secretion. We discuss the intracrine and autocrine/paracrine secretory responses evoked by cysLTs in eosinophils and in cell-free extracellular eosinophil crystalloid granules. We also discuss the importance of this finding in eosinophil immunobiology and speculate on its potential role(s) in eosinophilic diseases.

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Kamohara, Masazumi, Jun Takasaki, Mitsuyuki Matsumoto, Shun-ichiro Matsumoto, Tetsu Saito, Takatoshi Soga, Hitoshi Matsushime, and Kiyoshi Furuichi. "Functional Characterization of Cysteinyl Leukotriene CysLT2 Receptor on Human Coronary Artery Smooth Muscle Cells." Biochemical and Biophysical Research Communications 287, no. 5 (October 2001): 1088–92. http://dx.doi.org/10.1006/bbrc.2001.5695.

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Sekioka, Tomohiko, Michiaki Kadode, Yasuo Yonetomi, Akihiro Kamiya, Manabu Fujita, Takeshi Nabe, and Kazuhito Kawabata. "CysLT2 receptor activation is involved in LTC4-induced lung air-trapping in guinea pigs." European Journal of Pharmacology 794 (January 2017): 147–53. http://dx.doi.org/10.1016/j.ejphar.2016.11.036.

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Ballerini, P., R. Ciccarellf, F. Caciagli, M. P. Rathbone, E. S. Werstiuk, U. Traversa, S. Buccella, et al. "P2X7 Receptor Activation in Rat Brain Cultured Astrocytes Increases the Biosynthetic Release of Cysteinyl Leukotrienes." International Journal of Immunopathology and Pharmacology 18, no. 3 (July 2005): 417–30. http://dx.doi.org/10.1177/039463200501800303.

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Astrocytes have been recognized as important elements in controlling inflammatory as well as immune processes in the central nervous system (CNS). Recently, glial cells have been shown to produce cysteinyl leukotrienes (CysLTs) which are known lipid mediators of inflammation and whose extracellular concentrations rise under different pathological conditions in the brain. In the same conditions also extracellular concentrations of ATP dramatically increase reaching levels able to activate P2X7 ionotropic receptors for which an emerging role in neuroinflammation and neurodegeneration has been claimed. RT-PCR analysis showed that primary cultures of rat brain astrocytes express P2X7 receptors. Application of the selective P2X7 agonist benzoyl-benzolyATP (BzATP) markedly increased [Ca2+]i which was mediated by a calcium influx from the extracellular milieu. The P2X7 antagonist, oATP, suppressed the BzATP-induced calcium increase. Consistent with the evidence that increased calcium levels activate the leukotriene biosynthetic pathway, challenge of astrocytes with either the calcium ionophore A23187 or BzATP significantly increased CysLT production and the cell pre-treatment with EGTA abolished these effects. Again the P2X7 antagonist prevented the BzATP-mediated CysLT efflux, whereas the astrocyte pre-treatment with MK-571, a CysLT, receptor antagonist, was ineffective. The astrocyte pre-treatment with a cocktail of inhibitors of ATP binding cassette (ABC) proteins reduced the BzATP-mediated CysLT production confirming that ABC transporters are involved in the release of CysLTs. The astrocyte P2X7-evoked rise of CysLT efflux was abolished in the presence of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP) whose expression, along with that of 5′-lipoxygenase (5-LO) was reported by Northern Blot analysis. The stimulation of P2X7 induced an up-regulation of FLAP mRNA that was reduced by the antagonist oATP. These data suggest that in rat brain cultured astrocytes P2X7 ATP receptors may participate in the control of CysLT release thus further supporting a role for extracellular ATP as an integral component of the inflammatory brain response.

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Capra, Valérie, Chiara Carnini, Maria Rosa Accomazzo, Antonio Di Gennaro, Marco Fiumicelli, Emanuele Borroni, Ivan Brivio, et al. "Autocrine activity of cysteinyl leukotrienes in human vascular endothelial cells: Signaling through the CysLT2 receptor." Prostaglandins & Other Lipid Mediators 120 (July 2015): 115–25. http://dx.doi.org/10.1016/j.prostaglandins.2015.03.007.

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Zhang, Xia-Yan, Xiao-Rong Wang, Dong-Min Xu, Shu-Ying Yu, Qiao-Juan Shi, Li-Hui Zhang, Lu Chen, et al. "HAMI 3379, a CysLT2 Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation." Journal of Pharmacology and Experimental Therapeutics 346, no. 2 (June 7, 2013): 328–41. http://dx.doi.org/10.1124/jpet.113.203604.

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Liu, Pinggang, Derek A. Misurski, and Venkat Gopalakrishnan. "Cysteinyl leukotriene-dependent [Ca2+]iresponses to angiotensin II in cardiomyocytes." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 4 (April 1, 2003): H1269—H1276. http://dx.doi.org/10.1152/ajpheart.00303.2002.

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With the use of fura 2 measurements in multiple and single cells, we examined whether cysteinyl leukotrienes (CysLT) mediate angiotensin II (ANG II)-evoked increases in cytosolic free Ca2+ concentration ([Ca2+]i) in neonatal rat cardiomyocytes. ANG II-evoked CysLT release peaked at 1 min. The angiotensin type 1 (AT1) antagonist losartan, but not the AT2antagonist PD-123319, attenuated the elevations in [Ca2+]i and CysLT levels evoked by ANG II. Vasopressin and endothelin-1 increased [Ca2+]i but not CysLT levels. The 5-lipoxygenase (5-LO) inhibitor AA-861 and the CysLT1-selective antagonist MK-571 reduced the maximal [Ca2+]i responses to ANG II but not to vasopressin and endothelin-1. While MK-571 reduced the responses to leukotriene D4 (LTD4), the dual CysLT antagonist BAY-u9773 completely blocked the [Ca2+]i elevation to both LTD4and LTC4. These data confirm that ANG II-evoked increases, but not vasopressin- and endothelin-1-evoked increases, in [Ca2+]i involve generation of the 5-lipoxygenase metabolite CysLT. The inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] antagonist 2-aminoethoxydiphenyl borate attenuated the [Ca2+]i responses to ANG II and LTD4. Thus AT1 receptor activation by ANG II is linked to CysLT-mediated Ca2+ release from Ins(1,4,5)P3-sensitive intracellular stores to augment direct ANG II-evoked Ca2+ mobilization in rat cardiomyocytes.

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Yang, Guochang, Angela Haczku, Hang Chen, Viviane Martin, Helen Galczenski, Yaniv Tomer, Christopher R. Van Beisen, Jilly F. Evans, Reynold A. Panettieri, and Colin D. Funk. "Transgenic smooth muscle expression of the human CysLT1 receptor induces enhanced responsiveness of murine airways to leukotriene D4." American Journal of Physiology-Lung Cellular and Molecular Physiology 286, no. 5 (May 2004): L992—L1001. http://dx.doi.org/10.1152/ajplung.00367.2003.

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Cysteinyl leukotrienes (CysLTs) exert potent proinflammatory actions and contribute to many of the symptoms of asthma. Using a model of allergic sensitization and airway challenge with Aspergillus fumigatus ( Af), we have found that Th2-type inflammation and airway hyperresponsiveness (AHR) to methacholine (MCh) were associated with increased LTD4 responsiveness in mice. To explore the importance of increased CysLT signaling in airway smooth muscle function, we generated transgenic mice that overexpress the human CysLT1 receptor (hCysLT1R) via the α-actin promoter. These receptors were expressed abundantly and induced intracellular calcium mobilization in airway smooth muscle cells from transgenic mice. Force generation in tracheal ring preparations ex vivo and airway reactivity in vivo in response to LTD4 were greatly amplified in hCysLT1R-overexpressing mice, indicating that the enhanced signaling induces coordinated functional changes of the intact airway smooth muscle. The increase of AHR imposed by overexpression of the hCysLT1R was greater in transgenic BALB/c mice than in transgenic B6 × SJL mice. In addition, sensitization- and challenge-induced increases in airway responsiveness were significantly greater in transgenic mice than that of nontransgenic mice compared with their respective nonsensitized controls. The amplified AHR in sensitized transgenic mice was not due to an enhanced airway inflammation and was not associated with similar enhancement in MCh responsiveness. These results indicate that a selective hCysLT1R-induced contractile mechanism synergizes with allergic AHR. We speculate that hCysLT1R signaling contributes to a hypercontractile state of the airway smooth muscle.

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Bankova, Lora G., Juying Lai, Eri Yoshimoto, Joshua A. Boyce, K. Frank Austen, Yoshihide Kanaoka, and Nora A. Barrett. "Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99." Proceedings of the National Academy of Sciences 113, no. 22 (May 16, 2016): 6242–47. http://dx.doi.org/10.1073/pnas.1605957113.

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Cysteinyl leukotrienes (cysLTs), leukotriene C4 (LTC4), LTD4, and LTE4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE4, the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE4 that mediates cutaneous vascular permeability. Here we demonstrate that a single intranasal exposure to extract from the respiratory pathogen Alternaria alternata elicits profound epithelial cell (EpC) mucin release and submucosal swelling in the nasal mucosa of mice that depends on cysLTs, as it is absent in mice deficient in the terminal enzyme for cysLT biosynthesis, LTC4 synthase (LTC4S). These mucosal changes are associated with mast cell (MC) activation and absent in MC-deficient mice, suggesting a role for MCs in control of EpC function. Of the three CysLTRs, only GPR99-deficient mice are fully protected from EpC mucin release and swelling elicited by Alternaria or by intranasal LTE4. GPR99 expression is detected on lung and nasal EpCs, which release mucin to doses of LTE4 one log lower than that required to elicit submucosal swelling. Finally, mice deficient in MCs, LTC4S, or GPR99 have reduced baseline numbers of goblet cells, indicating an additional function in regulating EpC homeostasis. These results demonstrate a novel role for GPR99 among CysLTRs in control of respiratory EpC function and suggest that inhibition of LTE4 and of GPR99 may have therapeutic benefits in asthma.

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Kim, Nancy D., and Andrew D. Luster. "Regulation of Immune Cells by Eicosanoid Receptors." Scientific World JOURNAL 7 (2007): 1307–28. http://dx.doi.org/10.1100/tsw.2007.181.

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Eicosanoids are potent, bioactive, lipid mediators that regulate important components of the immune response, including defense against infection, ischemia, and injury, as well as instigating and perpetuating autoimmune and inflammatory conditions. Although these lipids have numerous effects on diverse cell types and organs, a greater understanding of their specific effects on key players of the immune system has been gained in recent years through the characterization of individual eicosanoid receptors, the identification and development of specific receptor agonists and inhibitors, and the generation of mice genetically deficient in various eicosanoid receptors. In this review, we will focus on the receptors for prostaglandin D2, DP1and DP2/CRTH2; the receptors for leukotriene B4, BLT1and BLT2; and the receptors for the cysteinyl leukotrienes, CysLT1and CysLT2, by examining their specific effects on leukocyte subpopulations, and how they may act in concert towards the development of immune and inflammatory responses.

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Wunder, F., H. Tinel, R. Kast, A. Geerts, EM Becker, P. Kolkhof, J. Hütter, J. Ergüden, and M. Härter. "Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT2) receptor." British Journal of Pharmacology 160, no. 2 (March 5, 2010): 399–409. http://dx.doi.org/10.1111/j.1476-5381.2010.00730.x.

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Pillai, Sreekumar G., Diane J. Cousens, Ashley A. Barnes, Peter T. Buckley, Mathias N. Chiano, Louise K. Hosking, Lee-Ann Cameron, et al. "A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma." Pharmacogenetics 14, no. 9 (September 2004): 627–33. http://dx.doi.org/10.1097/00008571-200409000-00007.

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Dong, Xiaowu, Yanmei Zhao, Xueqin Huang, Kana Lin, Jianzhong Chen, Erqing Wei, Tao Liu, and Yongzhou Hu. "Structure-based drug design using GPCR homology modeling: Toward the discovery of novel selective CysLT2 antagonists." European Journal of Medicinal Chemistry 62 (April 2013): 754–63. http://dx.doi.org/10.1016/j.ejmech.2013.01.041.

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Laroche, Dominique, Pierre Léturgie, Delphine Mariotte, Yann Ollivier, Jean-Luc Hanouz, Brigitte Le Mauff, and Jean-Jacques Parienti. "In Vivo Cysteinyl Leukotriene Release in Allergic and Nonallergic Immediate Hypersensitivity Reactions during Anesthesia." Anesthesiology 126, no. 5 (May 1, 2017): 834–41. http://dx.doi.org/10.1097/aln.0000000000001600.

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Abstract Background Immediate hypersensitivity reactions occurring during anesthesia are classified as allergic when skin tests and mast cell tryptase are positive and as nonallergic when negative results are obtained. Cysteinyl leukotrienes (cysLTs) are potent mediators synthesized by mast cell and eosinophil that induce bronchial constriction. They could play a role in hypersensitivity reactions. Methods cysLT C4, D4, and E4 concentrations were measured by a competition immunoassay in serial plasma samples obtained prospectively from 21 anesthetized controls and retrospectively from 34 patients who reacted at induction of anesthesia (24 with allergic and 10 with nonallergic reactions). Results In controls, the median (interquartile range) cysLT concentration was 0.83 (0.69 to 1.02) μg/l before anesthesia and was unchanged 30 min, 6 h, and 24 h afterward. In the patients with allergic reactions, the values were highly increased 30 to 60 min after the reaction (17.9 [7.8 to 36.0] μg/l), while the patients with nonallergic reactions had less increased values (7.3 [3.0 to 11.5] μg/l). The difference between the three groups was significant (P < 0.0001). Increased values persisted during the 24 h of observation. Concentrations were significantly higher in patients with bronchospasm (P = 0.016). Conclusions cysLTs appear to be an important mediator of allergic and nonallergic immediate hypersensitivity reactions. These findings might open a new field for management of patients with hypersensitivity reactions, especially nonallergic ones.

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Laidlaw, Tanya M., Molly S. Kidder, Neil Bhattacharyya, Wei Xing, Shiliang Shen, Ginger L. Milne, Mariana C. Castells, Heng Chhay, and Joshua A. Boyce. "Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes." Blood 119, no. 16 (April 19, 2012): 3790–98. http://dx.doi.org/10.1182/blood-2011-10-384826.

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Abstract Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A4 to LTC4, the parent cysLT, through the terminal enzyme LTC4 synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC4 synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC4 generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE4 levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.

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Shirasaki, Hideaki, Etsuko Kanaizumi, Nobuhiko Seki, Manabu Fujita, and Tetsuo Himi. "Mechanisims of asthma and allergic disease – 1084. Localization and up-regulation of CysLT2 receptorin perennial allergic rhinitis." World Allergy Organization Journal 6 (2013): P80. http://dx.doi.org/10.1186/1939-4551-6-s1-p80.

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Journal articles on the topic 'CysLT2'

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