The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130–fraction constant led to suppression of Th2 cells in the lung. By contrast, blockade of mIL-6R induced local expansion of Foxp3-positive CD4+CD25+ Tregs with increased immunosuppressive capacities. CD4+CD25+ but not CD4+CD25– lung T cells selectively expressed the IL-6R α chain and showed IL-6–dependent STAT-3 phosphorylation. Finally, in an in vivo transfer model of asthma in immunodeficient Rag1 mice, CD4+CD25+ T cells isolated from anti–IL-6R antibody–treated mice exhibited marked immunosuppressive and antiinflammatory functions. IL-6 signaling therefore controls the balance between effector cells and Tregs in the lung by means of different receptor components. Furthermore, inhibition of IL-6 signaling emerges as a novel molecular approach for the treatment of allergic asthma.
Aysefa Doganci, Tatjana Eigenbrod, Norbert Krug, George T. De Sanctis, Michael Hausding, Veit J. Erpenbeck, El-Bdaoui Haddad, Edgar Schmitt, Tobias Bopp, Karl-J. Kallen, Udo Herz, Steffen Schmitt, Cornelia Luft, Olaf Hecht, Jens M. Hohlfeld, Hiroaki Ito, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tadamitsu Kishimoto, Stefan Rose-John, Harald Renz, Markus F. Neurath, Peter R. Galle, Susetta Finotto
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Journal of immunology (Baltimore, Md. : 1950) | 2009 |
Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma
YA Bochkov, KM Hanson, S Keles, RA Brockman-Schneider, NN Jarjour, JE Gern |
Mucosal Immunology | 2009 |
Genetic ancestry modifies pharmacogenetic gene–gene interaction for asthma
Corvol H, De Giacomo A, Eng C, Seibold M, Ziv E, Chapela R, Rodriguez-Santana JR, Rodriguez-Cintron W, Thyne S, Watson HG, Meade K, LeNoir M, Avila PC, Choudhry S, Burchard EG |
Pharmacogenetics and Genomics | 2009 |
Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting OX40L and suppressing antigen-specific Foxp3+ T regulatory cells
W Duan, T So, M Croft |
Journal of immunology (Baltimore, Md. : 1950) | 2008 |
Psychological Factors in Asthma
RJ Lieshout, G MacQueen |
Allergy Asthma & Clinical Immunology | 2008 |
Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas
EC Brantley, EN Benveniste |
Molecular cancer research : MCR | 2008 |
Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation
O Haworth, M Cernadas, R Yang, CN Serhan, BD Levy |
Nature Immunology | 2008 |
New drugs targeting Th2 lymphocytes in asthma
G Caramori, D Groneberg, K Ito, P Casolari, IM Adcock, A Papi |
Journal of occupational medicine and toxicology (London, England) | 2008 |
TARC and RANTES enhance antitumor immunity induced by the GM-CSF-transduced tumor vaccine in a mouse tumor model
H Inoue, M Iga, M Xin, S Asahi, T Nakamura, R Kurita, M Nakayama, Y Nakazaki, K Takayama, Y Nakanishi, K Tani |
Cancer Immunology, Immunotherapy | 2008 |
(R)-albuterol decreases immune responses: role of activated T cells
MA Ferrada, EL Gordon, KY Jen, HZ He, X Lu, LM Barone, S Amirifeli, DL Perkins, PW Finn |
Respiratory Research | 2008 |
Interleukin-6 is crucial for recall of influenza-specific memory CD4 T cells
MP Longhi, K Wright, SN Lauder, MA Nowell, GW Jones, AJ Godkin, SA Jones, AM Gallimore |
PLoS pathogens | 2008 |
Alveolar macrophages from allergic lungs are not committed to a pro-allergic response and can reduce airway hyperresponsiveness following ex vivo culture
P Pouliot, A Spahr, É Careau, V Turmel, EY Bissonnette |
Clinical & Experimental Allergy | 2008 |
Vγ1+ γδ T cells reduce IL-10-producing CD4+CD25+ T cells in the lung of ovalbumin-sensitized and challenged mice
YS Hahn, XY Ji, SI Woo, YK Choi, MS Song, KS Shin, N Jin, RL O’Brien, WK Born |
Immunology Letters | 2008 |
Regulatory T cells and their molecular markers in peripheral blood of the patients with systemic lupus erythematosus
S Hu, W Xiao, F Kong, D Ke, R Qin, M Su |
Journal of Huazhong University of Science and Technology [Medical Sciences] | 2008 |
Prospective Study of Inhaled Corticosteroid Use, Cardiovascular Mortality, and All-Cause Mortality in Asthmatic Women
CA Camargo, RG Barr, R Chen, FE Speizer |
Chest | 2008 |
Cutting edge: soluble IL-6R is produced by IL-6R ectodomain shedding in activated CD4 T cells.
Briso EM, Dienz O, Rincon M |
Journal of immunology (Baltimore, Md. : 1950) | 2008 |
Immunosurveillance of Lung Melanoma Metastasis in EBI-3-Deficient Mice Mediated by CD8+ T Cells
Sauer KA, Maxeiner JH, Karwot R, Scholtes P, Lehr HA, Birkenbach M, Blumberg RS, Finotto S |
Journal of immunology (Baltimore, Md. : 1950) | 2008 |
Series overview: Harnessing the immune system to treat cancer
Nina Bhardwaj |
Journal of Clinical Investigation | 2007 |
Selection of probiotic bacteria for prevention of allergic diseases: immunomodulation of neonatal dendritic cells
LE Niers, MO Hoekstra, HM Timmerman, NO van Uden, PM de Graaf, HH Smits, JL Kimpen, GT Rijkers |
Clinical & Experimental Immunology | 2007 |
Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo
B Coles, CA Fielding, S Rose-John, J Scheller, SA Jones, VB O'Donnell |
The American Journal of Pathology | 2007 |
Nonredundant roles for Stat5a/b in directly regulating Foxp3
Z Yao, Y Kanno, M Kerenyi, G Stephens, L Durant, WT Watford, A Laurence, GW Robinson, EM Shevach, R Moriggl, L Hennighausen, C Wu, JJ O'Shea |
Blood | 2007 |
Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation
T Korn, J Reddy, W Gao, E Bettelli, A Awasthi, TR Petersen, BT Bäckström, RA Sobel, KW Wucherpfennig, TB Strom, M Oukka, VK Kuchroo |
Nature Medicine | 2007 |
Unique Gene Expression Profiles in Infants Vaccinated with Different Strains of Mycobacterium bovis Bacille Calmette-Guérin
B Wu, C Huang, L Garcia, AP de Leon, JS Osornio, M Bobadilla-del-Valle, L Ferreira, S Canizales, P Small, M Kato-Maeda, AM Krensky, C Clayberger |
Infection and immunity | 2007 |
Concentration of soluble interleukin-6 receptors in tears of allergic conjunctival disease patients.
Shoji J, Kawaguchi A, Gotoh A, Inada N, Sawa M |
Japanese Journal of Ophthalmology | 2007 |
Interleukin-10-Secreting regulatory T cells in allergy and asthma
Z Urry, E Xystrakis, CM Hawrylowicz |
Current Allergy and Asthma Reports | 2006 |
Interleukin-6 and its receptor: from bench to bedside
J Scheller, S Rose-John |
Medical Microbiology and Immunology | 2006 |
The role of immune tolerance in asthma pathogenesis
KG Tournoy, S Provoost, CV Hove, G Joos |
Current Allergy and Asthma Reports | 2006 |
Distinct roles for IL-6 and IL-12p40 in mediating protection againstLeishmania donovani and the expansion of IL-10+ CD4+ T cells
S Stäger, A Maroof, S Zubairi, SL Sanos, M Kopf, PM Kaye |
European Journal of Immunology | 2006 |
Dysfunctional T regulatory cells in multiple myeloma
RH Prabhala, P Neri, JE Bae, P Tassone, MA Shammas, CK Allam, JF Daley, D Chauhan, E Blanchard, HS Thatte, KC Anderson, NC Munshi |
Blood | 2006 |
Antibody array-generated cytokine profiles of tears of patients with vernal keratoconjunctivitis or giant papillary conjunctivitis.
Shoji J, Inada N, Sawa M |
Japanese Journal of Ophthalmology | 2006 |
The role of the FOXP3 transcription factor in the immune regulation of allergic asthma
CB Schmidt-Weber, K Blaser |
Current Allergy and Asthma Reports | 2005 |
Regulatory T cells and IL-10 in allergic inflammation: Figure. 1
CM Hawrylowicz |
Journal of Experimental Medicine | 2005 |
Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4 + CD25 + regulatory T cells is interleukin 10 dependent
J Kearley, JE Barker, DS Robinson, CM Lloyd |
Journal of Experimental Medicine | 2005 |
Pathological role of IL-6 in the experimental allergic bronchial asthma in mice.
Doganci A, Sauer K, Karwot R, Finotto S |
Clinical Reviews in Allergy & Immunology | 2005 |