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2 Production in Response to Prostaglandin D for Exaggerated Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2 This information is current as Luzheng Xue, Anna Barrow, Vicki M. Fleming, Michael G. of September 27, 2021. Hunter, Graham Ogg, Paul Klenerman and Roy Pettipher J Immunol 2012; 188:694-702; Prepublished online 14 December 2011; doi: 10.4049/jimmunol.1102474 http://www.jimmunol.org/content/188/2/694 Downloaded from References This article cites 59 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/188/2/694.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2 Luzheng Xue,* Anna Barrow,† Vicki M. Fleming,‡ Michael G. Hunter,† Graham Ogg,*,x Paul Klenerman,*,‡ and Roy Pettipher† PGD2 exerts a number of proinflammatory responses through a high-affinity interaction with chemoattractant receptor- homologous molecule expressed on Th2 cells (CRTH2) and has been detected at high concentrations at sites of allergic inflam- mation. Because cysteinyl leukotrienes (cysLTs) are also produced during the allergic response, we investigated the possibility that cysLTs may modulate the response of human Th2 cells to PGD2. PGD2 induced concentration-dependent Th2 cytokine production in the absence of TCR stimulation. Leukotrienes D4 and E4 (LTE4) also stimulated the cytokine production but were much less Downloaded from active than PGD2. However, when combined with PGD2, cysLTs caused a greater than additive enhancement of the response, with LTE4 being most effective in activating Th2 cells. LTE4 enhanced calcium mobilization in response to PGD2 in Th2 cells without affecting endogenous PGD2 production or CRTH2 receptor expression. The effect of LTE4 was inhibited by montelukast but not by the P2Y12 antagonist methylthioadenosine 59-monophosphate. The enhancing effect was also evident with endogenous cysLTs produced from immunologically activated mast cells because inhibition of cysLT action by montelukast or cysLT synthesis by MK886, an inhibitor of 5-lipoxygenase–activating protein, reduced the response of Th2 cells to the levels produced by PGD2 alone. http://www.jimmunol.org/ These findings reveal that cysLTs, in particular LTE4, have a significant proinflammatory impact on T cells and demonstrate their effects on Th2 cells are mediated by a montelukast-sensitive receptor. The Journal of Immunology, 2012, 188: 694–702. oth PGD2 and cysteinyl leukotrienes (cysLTs) are prod- kine release in transgenic mice overexpressing PGD2 synthase (9). ucts of the oxidative metabolism of arachidonic acid and Two distinct G protein-coupled receptors have been identified as B have been detected in high concentrations at sites of al- PGD2 receptors: D prostanoid receptor 1 and chemoattractant recep- lergic inflammation and play central roles in promoting airway tor-homologous molecule expressed on Th2 cells (CRTH2). In inflammation and deterioration in lung function, often acting in recent years, increasing evidence suggests that through its action by guest on September 27, 2021 concert (1, 2). on CRTH2, PGD2 elicits many proinflammatory responses in PGD2, produced by the activity of the cyclooxygenase enzymes, leukocytes, including chemotaxis of eosinophils, basophils, and is the major prostanoid released from mast cells during an allergic Th2 cells (10, 11), cytokine production by Th2 cells (12, 13), and response (3, 4), although macrophages (5), dendritic cells (6), and proinflammatory protein expression by eosinophils and Th2 cells + CD4 Th2 lymphocytes (7, 8) may contribute to PGD2 production (12, 14). Our recent studies also demonstrated that activation of in some circumstances. A significant contribution of PGD2 to the CRTH2 suppresses Th2 cell apoptosis (15), a process that is likely development of allergic inflammation has been suggested by the to impede the resolution of allergic inflammation. Allergic re- observations of enhanced eosinophilic lung inflammation and cyto- sponses mediated by IgE, mast cells, Th2 cells, and eosinophils are dramatically reduced in mice in which CRTH2 is genetically *Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, ablated or by small molecule CRTH2 antagonists (16–19). An- † Oxford OX3 9DU, United Kingdom; Oxagen Ltd., Abingdon OX14 4RY, United tagonism of CRTH2 is currently being considered as a potentially Kingdom; ‡Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom; and xMedical Re- useful approach for the treatment of allergic diseases, including search Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, asthma, rhinitis, and atopic dermatitis (20). John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom CysLTs, including cysteinyl leukotrienes C4 (LTC4), D4 (LTD4), Received for publication August 29, 2011. Accepted for publication November 10, and E (LTE ), are derived from the 5-lipoxygenase pathway 2011. 4 4 of the arachidonic acid metabolism (21, 22). LTC is formed by This work was supported in part by a grant from the Oxford Biomedical Research 4 Centre (to L.X., P.K., and G.O.) and the James Trust Grant from the British Medical conjugation of LTA4 with reduced glutathione and after extra- Association (to G.O., P.K., and L.X.), with additional funding from the Wellcome cellular export is converted to LTD4 and then the stable metabolite Trust (Grant WT091663MA to P.K. and V.M.F.), the Oxford Martin School (to P.K.), and the Medical Research Council (to G.O.). LTE4 by sequential enzymatic removal of glutamic acid followed by glycine. Two G protein-coupled receptors for LTs have been Address correspondence and reprint requests to Dr. Luzheng Xue, Oxford Biomed- ical Research Centre, NDM Experimental Medicine, John Radcliffe Hospital, Uni- cloned, characterized, and designated as CysLT1 and CysLT2 (23– versity of Oxford, Oxford OX3 9DU, United Kingdom. E-mail address: luzheng.xue@ 25). LTD4 binds CysLT1 with higher affinity than LTC4, whereas ndm.ox.ac.uk CysLT2 binds these cysLTs with equal affinity. LTE4 has only Abbreviations used in this article: CHO, Chinese hamster ovary; CRTH2, chemo- attractant receptor-homologous molecule expressed on Th2 cells; cysLT, cysteinyl weak activity on either CysLT1 (23, 24) or CysLT2 (25, 26) and leukotriene; LTC4, leukotriene C4;LTD4, leukotriene D4;LTE4, leukotriene E4; has therefore been generally considered to be a stable inactive 2MeS, 2-methylthioadenosine 59-monophosphate; PTX, pertussis toxin; qPCR, breakdown product, although there is accumulating evidence that real-time quantitative PCR. LTE4 can stimulate inflammatory responses through mechanisms Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 independent of CysLT1 or CysLT2 (27–31). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102474 The Journal of Immunology 695 CysLT1 mediates bronchoconstriction and also a range of The cells were pretreated with 5 mg/ml purified human myeloma IgE for 4 proinflammatory effects including activation and migration of d, washed, and then sensitized passively with fresh IgE (5 mg/ml) for 2 h. leukocytes (21, 32, 33), whereas CysLT may mediate the vaso- The cells were washed once with medium in absence or presence of 10 mM 2 diclofenac, 10 mM MK886, or both and then continued to be incubated active effects of LTC4 and LTD4. The leukotriene antagonists with medium or challenged with goat anti-human IgE (1 mg/ml) in the approved for use in asthma and allergic rhinitis, most notably presence or absence of diclofenac, MK886, or both for 1 h. The super- montelukast, block the action of cysLTs (predominantly LTD4)on natants of the cells were collected and measured for PGD2 using a PGD2– CysLT but do not inhibit CysLT -mediated effects. Monotherapy MOX enzyme immunoassay kit and LTE4 using a LTE4 enzyme immu- 1 2 noassay kit according to the manufacturer’s instructions. The supernatants with montelukast thereby inhibits the CysLT1-mediated broncho- were aliquoted and stored at 280˚C until used as mast cell supernatants for constrictor element of asthma, but its anti-inflammatory activity the treatment of Th2 cells. and, consequently, clinical efficacy are modest compared with that + + of inhaled steroids (34). However, in patients with asthma not Human CRTH2 CD4 Th2 cell culture and treatment sufficiently controlled with inhaled steroids alone, add-on therapy Human CRTH2+CD4+ Th2 cells were prepared as described in our previous with montelukast to a constant
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