Cytokine-Directed Therapies in Asthma

Total Page:16

File Type:pdf, Size:1020Kb

Cytokine-Directed Therapies in Asthma CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Allergology International (2003) 52: 53–63 Review Article Cytokine-directed therapies in asthma Peter J Barnes National Heart and Lung Institute, Imperial College, London, UK ABSTRACT Multiple cytokines and chemokines have been impli- cated in the pathophysiology of asthma.1 There is now Multiple cytokines play a critical role in orchestrating an intensive search for more specific therapies in and perpetuating inflammation in asthma and several asthma. Inhibitors of cytokines and chemokines figure specific cytokine and chemokine inhibitors are now in prominently in these novel therapeutic approaches2 development as future therapy. Anti-interleukin (IL)-5 (Table 1). antibodies markedly reduce peripheral blood and airway eosinophils, but do not appear to be effective in symptomatic asthma. Inhibition of IL-4, despite prom- STRATEGIES FOR INHIBITING CYTOKINES ising early results in asthma, has been discontinued There are several possible approaches to inhibiting and blocking IL-13 may be more effective. Inhibitory specific cytokines. These range from drugs that inhibit cytokines, such as IL-10, interferons and IL-12 are less cytokine synthesis (glucocorticoids, cyclosporine A, promising, because systemic delivery produces side- tacrolimus, rapamycin, mycophenolate, T helper 2 effects. Inhibition of tumor necrosis factor (TNF)-α may (Th2)-selective inhibitors), humanized blocking anti- be useful in severe asthma. Many chemokines are bodies to cytokines or their receptors, soluble receptors involved in the inflammatory response of asthma and to mop up secreted cytokines, small molecule receptor several small molecule inhibitors of chemokine recep- antagonists or drugs that block the signal transduction tors are in development. The CCR3 antagonists (which pathways activated by cytokine receptors. In contrast, block eosinophil chemotaxis) are in clinical develop- there are cytokines that themselves suppress the allergic ment for asthma. Because so many cytokines are inflammatory process and these may have therapeutic involved in asthma, drugs that inhibit the synthesis of potential in asthma.3 multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side-effects with these non-specific INHIBITION OF TH2 CYTOKINES inhibitors may be reduced by the inhaled route. The Th2 lymphocytes play a key role in orchestrating the eosinophilic inflammatory response in asthma, suggest- Key words: chemokines, interleukin-4, interleukin-5, ing that blocking the release or effects of these cytokines interleukin-10, interleukin-12, interleukin-13, tumor may have therapeutic potential. This has been strongly necrosis factor-α. supported by studies in experimental animals, including mice with deletion of the specific Th2 cytokine genes. INTRODUCTION Anti-interleukin-5 Cytokines play a critical role in the orchestration of chronic inflammation in all diseases, including asthma. Interleukin (IL)-5 plays an essential role in orchestrating the eosinophilic inflammation of asthma.4 In IL-5 gene knock-out mice, the eosinophilic response to allergen Correspondence: Professor PJ Barnes, Department of Thoracic and the subsequent airway hyperresponsiveness (AHR) Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. are markedly suppressed and yet animals have a normal Email: [email protected] survival, validating the strategy to inhibit IL-5. This has Received 18 February 2003. also been achieved using blocking antibodies to IL-5. 54 PJ BARNES Blocking antibodies to IL-5 inhibit eosinophilic inflam- several weeks and prevents eosinophil recruitment into mation and AHR in animal models of asthma, including the airways after allergen challenge in patients with mild primates.5 This blocking effect may last for up to asthma6 (Fig. 1). However, this treatment has no signifi- 3 months after a single intravenous injection of antibody cant effect on the early or late response to allergen in primates, making treatment of chronic asthma with challenge or on baseline AHR, suggesting that eosin- such a therapy a feasible proposition. Humanized mono- ophils may not be of critical importance for these clonal antibodies to IL-5 have been developed and a responses in humans (Fig. 2). A clinical study in patients single intravenous infusion of one of these antibodies with moderate to severe asthma who had not been (mepolizulab) markedly reduces blood eosinophils for controlled on inhaled corticosteroid therapy confirmed a Table 1 Cytokine modulators for asthma Anti-cytokines Inhibitory cytokines Chemokine inhibitors Cytokine synthesis inhibitors Anti-IL-5 IL-1 receptor antagonist CCR3 antagonists Corticosteroids Anti-IL-4 IL-10 CCR2 antagonists Immunomodulators Anti-IL-13 IL-12 CCR4 antagonists Phosphodiesterase-4 inhibitors Anti-IL-9 Interferons (IFN-α, IFN-γ) CCR8 antagonists NF-κB inhibitors (IKK2 inhibitors) Anti-IL-25 IL-18 CXCR2 antagonists p38 MAPK inhibitors Anti-IL-1 IL-23 CXCR4 antagonists Anti-TNF-α IL, interleukin; TNF-α, tumor necrosis factor-α; IFN, interferon; NF-κB, nuclear factor-κB; IKK, inhibitor of NF-κB kinase; MAPK, mitogen- activated protein kinase. Fig. 1 Effect of a humanized monoclonal antibody against interleukin-5 (mepolizumab) on circulating eosinophils in patients with mild asthma, demonstrating a profound and very prolonged inhibitory effect. (᭡), placebo (n = 8); ( ), 2.5 mg/kg mepolizumab (n = 8); (᭿), 10 mg/kg mepolizumab (n = 8). B/L, baseline; D, day; Wk, week. Adapted from Leckie et al.6 CYTOKINE-DIRECTED THERAPIES IN ASTHMA 55 Fig. 2 Effect of a humanized monoclonal antibody against interleukin (IL)-5 (mepomizulab) on (a) the early and late response to allergen (–––, IL-5 antibody; -----, placebo) and (b) airway hyperresponsiveness (ᮀ, placebo; ᭿, IL-5 antibody). FEV1, forced expiratory volume in 1 s. Adapted from Leckie et al.6 profound reduction in circulating eosinophils, but no α-chain and through large-scale throughput screening. significant improvement in either asthma symptoms or One such molecule, YM-90709, appears to be a rela- lung function.7 In both these studies, it would be tively selective inhibitor of IL-5-receptors.10 However, the expected that high doses of corticosteroids would lack of clinical benefit of anti-IL-5 antibodies has made improve these functional parameters.6,7 These surprising this a less attractive approach. It is possible that eosin- results question the critical role of eosinophils in asthma ophils are associated with more chronic aspects of and indicate that other strategies aimed at inhibiting asthma, such as airway remodeling, and, in mice, a eosinophilic inflammation may not be effective. More blocking anti-IL-5 antibody prevents the increased colla- recently, a biopsy study has demonstrated that anti-IL-5 gen deposition in airways associated with repeated aller- antibody, while profoundly reducing eosinophils in the gen exposure. circulation (by over 95%), is less effective at reducing eosinophils in bronchial biopsies (by approximately Anti-IL-4 50%), which may explain why this treatment is not clinically effective.8 Nevertheless, this suggests that Interleukin-4 is critical for the synthesis of IgE by blocking IL-5 is not likely to be a useful approach to B lymphocytes and is also involved in eosinophil recruit- asthma therapy. ment to the airways.11 A unique function of IL-4 is Somewhat similar findings have been reported previ- to promote differentiation of Th2 cells and, there- ously in some studies in mice, where anti-IL-5 antibodies fore, it acts at a proximal and critical site in the allergic reduced eosinophilic responses to allergen, but not AHR, response, making IL-4 an attractive target for inhibition. whereas AHR was reduced by anti-CD4 antibody, which Interleukin-4 blocking antibodies inhibit allergen- depletes Th cells9 and suggests that T cell-derived induced AHR, goblet cell metaplasia and pulmonary cytokines other than IL-5 must be playing a more impor- eosinophilia in a murine model.11 Therefore, inhibition of tant role in AHR. IL-4 may be effective in inhibiting allergic diseases and Non-peptidic IL-5 receptor antagonists would be an soluble humanized IL-4 receptors (sIL-4R) have been alternative strategy and there is a search for such com- tested in clinical trials. A single nebulized dose of sIL-4R pounds using molecular modeling of the IL-5 receptor prevents the fall in lung function induced by withdrawal of 56 PJ BARNES inhaled corticosteroids in patients with moderately severe where concentrations of IL-13 are much higher than asthma.12 Subsequent studies have demonstrated that those of IL-4. Humanized IL-13Rα2 is now in clinical weekly nebulization of sIL-4R improves asthma control development as a therapeutic approach for asthma. over a 12 week period.13 However, subsequent studies in patients with milder asthma proved disappointing Anti-IL-9 and this treatment has now been withdrawn. Another Interleukin-9 is a Th2 cytokine that may enhance approach is blockade of IL-4 receptors with a mutated Th2-driven inflammation and amplify mast cell mediator form of IL-4 (BAY 36-1677), which binds to and blocks release and IgE production.18 Interleukin-9 may also IL-4Rα and IL-13Rα1, thus blocking both IL-4 and enhance mucus hypersecretion. Interleukin-9 and its IL-13.14 This treatment has also been withdrawn. receptors show an increased expression in asthmatic Interleukin-4
Recommended publications
  • HIV-1 Tat Protein Mimicry of Chemokines
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 13153–13158, October 1998 Immunology HIV-1 Tat protein mimicry of chemokines ADRIANA ALBINI*, SILVANO FERRINI*, ROBERTO BENELLI*, SABRINA SFORZINI*, DANIELA GIUNCIUGLIO*, MARIA GRAZIA ALUIGI*, AMANDA E. I. PROUDFOOT†,SAMI ALOUANI†,TIMOTHY N. C. WELLS†, GIULIANO MARIANI‡,RONALD L. RABIN§,JOSHUA M. FARBER§, AND DOUGLAS M. NOONAN*¶ *Centro di Biotecnologie Avanzate, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, 10, 16132 Genoa, Italy; †Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, 14 chemin des Aulx, 1228 Plan-les Ouates, Geneva, Switzerland; ‡Dipartimento di Medicina Interna, Medicina Nucleare, University of Genova, Viale Benedetto XV, 6, 16132 Genoa, Italy; and §National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N228 MSC 1888, Bethesda, MD 20892 Edited by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved August 25, 1998 (received for review June 24, 1998) ABSTRACT The HIV-1 Tat protein is a potent chemoat- ceptors for some dual tropic HIV-1 strains (10, 11). A CCR2 tractant for monocytes. We observed that Tat shows conserved polymorphism has been found to correlate with delayed amino acids corresponding to critical sequences of the che- progression to AIDS (12, 13). mokines, a family of molecules known for their potent ability We report here that the HIV-1 Tat protein and the peptide to attract monocytes. Synthetic Tat and a peptide (CysL24–51) encompassing the cysteine-rich and core regions induce per- encompassing the ‘‘chemokine-like’’ region of Tat induced a tussis toxin sensitive Ca21 fluxes in monocytes.
    [Show full text]
  • Cytokine Modulators As Novel Therapies for Airway Disease
    Copyright #ERS Journals Ltd 2001 Eur Respir J 2001; 18: Suppl. 34, 67s–77s European Respiratory Journal DOI: 10.1183/09031936.01.00229901 ISSN 0904-1850 Printed in UK – all rights reserved ISBN 1-904097-20-0 Cytokine modulators as novel therapies for airway disease P.J. Barnes Cytokine modulators as novel therapies for airway disease. P.J. Barnes. #ERS Correspondence: P.J. Barnes Journals Ltd 2001. Dept of Thoracic Medicine ABSTRACT: Cytokines play a critical role in orchestrating and perpetuating National Heart & Lung Institute inflammation in asthma and chronic obstructive pulmonary disease (COPD), and Imperial College Dovehouse Street several specific cytokine and chemokine inhibitors are now in development for the future London SW3 6LY therapy of these diseases. UK Anti-interleukin (IL)-5 is very effective at reducing peripheral blood and airway Fax: 0207 3515675 eosinophil numbers, but does not appear to be effective against symptomatic asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in Keywords: Chemokine receptor asthma. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, cytokine as systemic delivery causes side-effects. Inhibition of tumour necrosis factor-a may be interleukin-4 useful in severe asthma and for treating severe COPD with systemic features. interleukin-5 interleukin-9 Many chemokines are involved in the inflammatory response of asthma and COPD interleukin-10 and several low-molecular-weight inhibitors of chemokine receptors are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which Received: March 26 2001 block neutrophil and monocyte chemotaxis) are in clinical development for the Accepted April 25 2001 treatment of asthma and COPD respectively.
    [Show full text]
  • CCR3, CCR5, Interleukin 4, and Interferon-Γ Expression on Synovial
    CCR3, CCR5, Interleukin 4, and Interferon-γ Expression on Synovial and Peripheral T Cells and Monocytes in Patients with Rheumatoid Arthritis RIIKKA NISSINEN, MARJATTA LEIRISALO-REPO, MINNA TIITTANEN, HEIKKI JULKUNEN, HANNA HIRVONEN, TIMO PALOSUO, and OUTI VAARALA ABSTRACT. Objective. To characterize cytokine and chemokine receptor profiles of T cells and monocytes in inflamed synovium and peripheral blood (PB) in patients with rheumatoid arthritis (RA) and other arthritides. Methods. We studied PB and synovial fluid (SF) samples taken from 20 patients with RA and 9 patients with other arthritides. PB cells from 8 healthy adults were used as controls. CCR3, CCR5, and intracellular interferon-γ (IFN-γ) and interleukin 4 (IL-4) expression in CD8+ and CD8– T cell populations and in CD14+ cells were determined with flow cytometry. Results. Expression of CCR5 and CCR3 by CD8–, CD8+ T cells and CD14+ monocytes was increased in SF compared to PB cells in patients with RA and other arthritides. The number of CD8+ T cells spontaneously expressing IL-4 and IFN-γ was higher in SF than in PB in RA patients. Spontaneous CCR5 expression was associated with intracellular IFN-γ expression in CD8+ T cells derived from SF in RA. In CD8– T cells the ratio of CCR5+/CCR3+ cells was increased in patients with RA compared to patients with other arthritides. The number of PB CD8– T cells expressing IFN-γ after mitogen stimulation was higher in controls than in patients. In PB monocytes the ratio of CCR5+/CCR3+ cells was increased in patients with RA compared to patients with other arthri- tides and controls.
    [Show full text]
  • Role of Chemokines in Hepatocellular Carcinoma (Review)
    ONCOLOGY REPORTS 45: 809-823, 2021 Role of chemokines in hepatocellular carcinoma (Review) DONGDONG XUE1*, YA ZHENG2*, JUNYE WEN1, JINGZHAO HAN1, HONGFANG TUO1, YIFAN LIU1 and YANHUI PENG1 1Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051; 2Medical Center Laboratory, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, P.R. China Received September 5, 2020; Accepted December 4, 2020 DOI: 10.3892/or.2020.7906 Abstract. Hepatocellular carcinoma (HCC) is a prevalent 1. Introduction malignant tumor worldwide, with an unsatisfactory prognosis, although treatments are improving. One of the main challenges Hepatocellular carcinoma (HCC) is the sixth most common for the treatment of HCC is the prevention or management type of cancer worldwide and the third leading cause of of recurrence and metastasis of HCC. It has been found that cancer-associated death (1). Most patients cannot undergo chemokines and their receptors serve a pivotal role in HCC radical surgery due to the presence of intrahepatic or distant progression. In the present review, the literature on the multi- organ metastases, and at present, the primary treatment methods factorial roles of exosomes in HCC from PubMed, Cochrane for HCC include surgery, local ablation therapy and radiation library and Embase were obtained, with a specific focus on intervention (2). These methods allow for effective treatment the functions and mechanisms of chemokines in HCC. To and management of patients with HCC during the early stages, date, >50 chemokines have been found, which can be divided with 5-year survival rates as high as 70% (3). Despite the into four families: CXC, CX3C, CC and XC, according to the continuous development of traditional treatment methods, the different positions of the conserved N-terminal cysteine resi- issue of recurrence and metastasis of HCC, causing adverse dues.
    [Show full text]
  • High Expression of the Chemokine Receptor CCR3 in Human Blood Basophils
    High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines. M Uguccioni, … , M Baggiolini, C A Dahinden J Clin Invest. 1997;100(5):1137-1143. https://doi.org/10.1172/JCI119624. Research Article Eosinophil leukocytes express high numbers of the chemokine receptor CCR3 which binds eotaxin, monocyte chemotactic protein (MCP)-4, and some other CC chemokines. In this paper we show that CCR3 is also highly expressed on human blood basophils, as indicated by Northern blotting and flow cytometry, and mediates mainly chemotaxis. Eotaxin and MCP-4 elicited basophil migration in vitro with similar efficacy as regulated upon activation normal T cells expressed and secreted (RANTES) and MCP-3. They also induced the release of histamine and leukotrienes in IL-3- primed basophils, but their efficacy was lower than that of MCP-1 and MCP-3, which were the most potent stimuli of exocytosis. Pretreatment of the basophils with a CCR3-blocking antibody abrogated the migration induced by eotaxin, RANTES, and by low to optimal concentrations of MCP-4, but decreased only minimally the response to MCP-3. The CCR3-blocking antibody also affected exocytosis: it abrogated histamine and leukotriene release induced by eotaxin, and partially inhibited the response to RANTES and MCP-4. In contrast, the antibody did not affect the responses induced by MCP-1, MCP-3, and macrophage inflammatory protein-1alpha, which may depend on CCR1 and CCR2, two additional receptors detected by Northern blotting with basophil RNA. This study demonstrates that CCR3 is the major receptor for eotaxin, RANTES, and MCP-4 in human basophils, and suggests that basophils and eosinophils, which are the characteristic […] Find the latest version: https://jci.me/119624/pdf High Expression of the Chemokine Receptor CCR3 in Human Blood Basophils Role in Activation by Eotaxin, MCP-4, and Other Chemokines Mariagrazia Uguccioni,* Charles R.
    [Show full text]
  • Colorectal Cancer-Infiltrating T Lymphocytes Display a Distinct
    Löfroos et al. Eur J Med Res (2017) 22:40 DOI 10.1186/s40001-017-0283-8 European Journal of Medical Research RESEARCH Open Access Colorectal cancer‑infltrating T lymphocytes display a distinct chemokine receptor expression profle Ann‑Britt Löfroos1,2†, Mohammad Kadivar2†, Sabina Resic Lindehammer1,2 and Jan Marsal1,2,3* Abstract Background: T lymphocytes exert important homeostatic functions in the healthy intestinal mucosa, whereas in case of colorectal cancer (CRC), infltration of T lymphocytes into the tumor is crucial for an efective anti-tumor immune response. In both situations, the recruitment mechanisms of T lymphocytes into the tissues are essential for the immunological functions deciding the outcome. The recruitment of T lymphocytes is largely dependent on their expression of various chemokine receptors. The aim of this study was to identify potential chemokine receptors involved in the recruitment of T lymphocytes to normal human colonic mucosa and to CRC tissue, respectively, by examining the expression of 16 diferent chemokine receptors on T lymphocytes isolated from these tissues. Methods: Tissues were collected from patients undergoing bowel resection for CRC. Lymphocytes were isolated through enzymatic tissue degradation of CRC tissue and nearby located unafected mucosa, respectively. The expres‑ sion of a broad panel of chemokine receptors on the freshly isolated T lymphocytes was examined by fow cytometry. Results: In the normal colonic mucosa, the frequencies of cells expressing CCR2, CCR4, CXCR3, and CXCR6 dif‑ fered signifcantly between ­CD4+ and ­CD8+ T lymphocytes, suggesting that the molecular mechanisms mediating T lymphocyte recruitment to the gut difer between ­CD4+ and ­CD8+ T lymphocytes.
    [Show full text]
  • The Receptor for TCA-3 Molecular Characterization of Murine CCR8 As
    Identification of CCR8 as the Specific Receptor for the Human β-Chemokine I-309: Cloning and Molecular Characterization of Murine CCR8 as the Receptor for TCA-3 This information is current as of September 23, 2021. Iñigo Goya, Julio Gutiérrez, Rosa Varona, Leonor Kremer, Angel Zaballos and Gabriel Márquez J Immunol 1998; 160:1975-1981; ; http://www.jimmunol.org/content/160/4/1975 Downloaded from References This article cites 51 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/160/4/1975.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 23, 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Identification of CCR8 as the Specific Receptor for the Human b-Chemokine I-309: Cloning and Molecular Characterization of Murine CCR8 as the Receptor for TCA-31 In˜igo Goya, Julio Gutie´rrez, Rosa Varona, Leonor Kremer, Angel Zaballos, and Gabriel Ma´rquez2 Chemokine receptor-like 1 (CKR-L1) was described recently as a putative seven-transmembrane human receptor with many of the structural features of chemokine receptors.
    [Show full text]
  • Human Dendritic Cells Chemokine Ligand 11) Receptor CCR3 By
    Expression of a Functional Eotaxin (CC Chemokine Ligand 11) Receptor CCR3 by Human Dendritic Cells This information is current as Sylvie Beaulieu, Davide F. Robbiani, Xixuan Du, Elaine of September 23, 2021. Rodrigues, Ralf Ignatius, Yang Wei, Paul Ponath, James W. Young, Melissa Pope, Ralph M. Steinman and Svetlana Mojsov J Immunol 2002; 169:2925-2936; ; doi: 10.4049/jimmunol.169.6.2925 Downloaded from http://www.jimmunol.org/content/169/6/2925 References This article cites 83 articles, 45 of which you can access for free at: http://www.jimmunol.org/content/169/6/2925.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 by guest on September 23, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Expression of a Functional Eotaxin (CC Chemokine Ligand 11) Receptor CCR3 by Human Dendritic Cells1,2,3 Sylvie Beaulieu,4* Davide F.
    [Show full text]
  • Inflammatory Chemokines in Atherosclerosis
    cells Review Inflammatory Chemokines in Atherosclerosis Selin Gencer 1,† , Bryce R. Evans 2,†, Emiel P.C. van der Vorst 1,3,4,5,‡ , Yvonne Döring 1,2,3,‡ and Christian Weber 1,3,6,7,*,‡ 1 Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany; [email protected] (S.G.); [email protected] (E.P.C.v.d.V.); [email protected] (Y.D.) 2 Department of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; [email protected] (B.R.E.); [email protected] (Y.D.) 3 German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany 4 Interdisciplinary Center for Clinical Research (IZKF), Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany 5 Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands 6 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands 7 Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany * Correspondence: [email protected] † These authors contributed equally to this manuscript and share first authorship. ‡ These authors contributed equally to this manuscript and share last authorship. Abstract: Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions.
    [Show full text]
  • Promoter Identification of a Functional CCR1 CCR3 Function, Expression in Atopy, and Responses: an Investigation of CCR1 And
    Variations in Eosinophil Chemokine Responses: An Investigation of CCR1 and CCR3 Function, Expression in Atopy, and Identification of a Functional CCR1 This information is current as Promoter of September 27, 2021. Rhian M. Phillips, Victoria E. L. Stubbs, Mandy R. Henson, Timothy J. Williams, James E. Pease and Ian Sabroe J Immunol 2003; 170:6190-6201; ; doi: 10.4049/jimmunol.170.12.6190 Downloaded from http://www.jimmunol.org/content/170/12/6190 References This article cites 43 articles, 24 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/170/12/6190.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Variations in Eosinophil Chemokine Responses: An Investigation of CCR1 and CCR3 Function, Expression in Atopy, and Identification of a Functional CCR1 Promoter1 Rhian M.
    [Show full text]
  • The Amino-Terminal Domain of the CCR2 Chemokine Receptor Acts As Coreceptor for HIV-1 Infection
    The amino-terminal domain of the CCR2 chemokine receptor acts as coreceptor for HIV-1 infection. J M Frade, … , G Real, C Martínez-A J Clin Invest. 1997;100(3):497-502. https://doi.org/10.1172/JCI119558. Research Article The chemokines are a homologous serum protein family characterized by their ability to induce activation of integrin adhesion molecules and leukocyte migration. Chemokines interact with their receptors, which are composed of a single- chain, seven-helix, membrane-spanning protein coupled to G proteins. Two CC chemokine receptors, CCR3 and CCR5, as well as the CXCR4 chemokine receptor, have been shown necessary for infection by several HIV-1 virus isolates. We studied the effect of the chemokine monocyte chemoattractant protein 1 (MCP-1) and of a panel of MCP-1 receptor (CCR2)-specific monoclonal antibodies (mAb) on the suppression of HIV-1 replication in peripheral blood mononuclear cells. We have compelling evidence that MCP-1 has potent HIV-1 suppressive activity when HIV-1-infected peripheral blood lymphocytes are used as target cells. Furthermore, mAb specific for the MCP-1R CCR2 which recognize the third extracellular CCR2 domain inhibit all MCP-1 activity and also block MCP-1 suppressive activity. Finally, a set of mAb specific for the CCR2 amino-terminal domain, one of which mimics MCP-1 activity, has a potent suppressive effect on HIV-1 replication in M- and T-tropic HIV-1 viral isolates. We conjecture a role for CCR2 as a coreceptor for HIV-1 infection and map the HIV-1 binding site to the amino-terminal part of this receptor.
    [Show full text]
  • Chemokine and Chemokine Receptor Profiles in Metastatic Salivary Adenoid Cystic Carcinoma ASHLEY C
    ANTICANCER RESEARCH 36 : 4013-4018 (2016) Chemokine and Chemokine Receptor Profiles in Metastatic Salivary Adenoid Cystic Carcinoma ASHLEY C. MAYS, XIN FENG, JAMES D. BROWNE and CHRISTOPHER A. SULLIVAN Department of Otolaryngology, Wake Forest School of Medicine, Winston Salem, NC, U.S.A. Abstract. Aim: To characterize the chemokine pattern in distant metastasis (2-5). According to Ko et al. , 75% of metastatic salivary adenoid cystic carcinoma (SACC). patients with initial nodal involvement eventually developed Materials and Methods: Real-time polymerase chain distant metastasis. Patients with lung metastasis have a poor reaction (RT-PCR) was used to compare chemokine and prognosis (6). chemokine receptor gene expression in two SACC cell lines: The development of distant metastatic disease is the chief SACC-83 and SACC-LM (lung metastasis). Chemokines and cause for mortality (7, 8). Primary treatment is complete receptor genes were then screened and their expression surgical resection when feasible with adjuvant radiotherapy. pattern characterized in human tissue samples of non- The role of chemotherapy is debatable. Treatment of recurrent SACC and recurrent SACC with perineural metastatic ACC has been difficult to date due to lack of invasion. Results: Expression of chemokine receptors specific targets for metastatic cells (1). Though the steps that C5AR1, CCR1, CCR3, CCR6, CCR7, CCR9, CCR10, must occur in the metastatic event are well characterized, it CXCR4, CXCR6, CXCR7, CCRL1 and CCRL2 were higher remains unclear why or how ACC cells ultimately “choose” in SACC-83 compared to SACC-LM. CCRL1, CCBP2, or are ”chosen” to migrate to a specific metastatic site. A CMKLR1, XCR1 and CXCR2 and 6 chemokine genes mounting body of evidence suggests that cytokine-like (CCL13, CCL27, CXCL14, CMTM1, CMTM2, CKLF) were molecules called chemokines play a significant role in more highly expressed in tissues of patients without tumor directing the cellular traffic in metastatic melanoma, lung, recurrence/perineural invasion compared to those with breast and ACC cancers (9-15).
    [Show full text]