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PMID: 15668741 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.

The Journal of clinical investigation ·Vol. 115 ·No. 2 ·2005-02-00 ·Pages 313-25

Doganci A, Eigenbrod T, Krug N, De Sanctis GT, Hausding M, Erpenbeck VJ, Haddad el-B, Lehr HA, Schmitt E, Bopp T, Kallen KJ, Herz U, Schmitt S, Luft C, Hecht O, Hohlfeld JM, Ito H, Nishimoto N, Yoshizaki K, Kishimoto T, Rose-John S, Renz H, Neurath MF, Galle PR, Finotto S

Abstract

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 alpha 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.

MeSH Terms
Adult Animals Antibodies/administration & dosage,immunology Asthma/immunology,pathology DNA-Binding Proteins/immunology Female Forkhead Transcription Factors Homeodomain Proteins/genetics,immunology Humans Hypersensitivity/immunology,pathology Inflammation/immunology,pathology Lung/immunology,pathology Male Mice Mice, Knockout Ovalbumin/metabolism Receptors, Cytokine/immunology Receptors, Interleukin-2/immunology Receptors, Interleukin-6/immunology STAT3 Transcription Factor Signal Transduction/drug effects,genetics,immunology Th2 Cells/immunology,pathology Trans-Activators/immunology
Chemicals
Antibodies DNA-Binding Proteins FOXP3 protein, human Forkhead Transcription Factors Foxp3 protein, mouse Homeodomain Proteins Receptors, Cytokine Receptors, Interleukin-2 Receptors, Interleukin-6 STAT3 Transcription Factor STAT3 protein, human Stat3 protein, mouse Trans-Activators cytokine receptor, GLM-R RAG-1 protein Ovalbumin
Authors & Affiliations
25 authors, click to expand affiliations / ORCID
Doganci Aysefa
Laboratory of Cellular and Molecular Immunology of the Lung, First Medical Clinic, University of Mainz, Mainz, Germany.
Eigenbrod Tatjana
Krug Norbert
De Sanctis George T
Hausding Michael
Erpenbeck Veit J
Haddad El-Bdaoui
Lehr Hans A
Schmitt Edgar
Bopp Tobias
Kallen Karl-J
Herz Udo
Schmitt Steffen
Luft Cornelia
Hecht Olaf
Hohlfeld Jens M
Ito Hiroaki
Nishimoto Norihiro
Yoshizaki Kazuyuki
Kishimoto Tadamitsu
Rose-John Stefan
Renz Harald
Neurath Markus F
Galle Peter R
Finotto Susetta
References (53)
53 references, click to expand
  1. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11924-8 PMID: 8265649
  2. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.
    J Clin Invest. 1999 Mar;103(6):779-88 PMID: 10079098
  3. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.
    Nature. 2002 Dec 5;420(6915):502-7 PMID: 12466842
  4. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial.
    Arthritis Rheum. 2002 Dec;46(12):3143-50 PMID: 12483717
  5. Protein kinase C delta associates with the interleukin-6 receptor subunit glycoprotein (gp) 130 via Stat3 and enhances Stat3-gp130 interaction.
    J Biol Chem. 2002 Dec 20;277(51):49134-42 PMID: 12361954
  6. Control of regulatory T cell development by the transcription factor Foxp3.
    Science. 2003 Feb 14;299(5609):1057-61 PMID: 12522256
  7. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.
    Science. 2003 Feb 14;299(5609):1033-6 PMID: 12532024
  8. Immunology. Regulating the regulators.
    Science. 2003 Feb 14;299(5609):1030-1 PMID: 12586934
  9. Local release of eosinophil peroxidase following segmental allergen provocation in asthma.
    Clin Exp Allergy. 2003 Mar;33(3):331-6 PMID: 12614447
  10. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
    Nat Immunol. 2003 Apr;4(4):330-6 PMID: 12612578
  11. An essential role for Scurfin in CD4+CD25+ T regulatory cells.
    Nat Immunol. 2003 Apr;4(4):337-42 PMID: 12612581
  12. Twenty-first century Foxp3.
    Nat Immunol. 2003 Apr;4(4):304-6 PMID: 12660726
  13. IL-6 production by pulmonary dendritic cells impedes Th1 immune responses.
    J Immunol. 2003 May 1;170(9):4457-64 PMID: 12707321
  14. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.
    Nat Med. 2003 May;9(5):582-8 PMID: 12669034
  15. SOCS3 negatively regulates IL-6 signaling in vivo.
    Nat Immunol. 2003 Jun;4(6):540-5 PMID: 12754505
  16. IL-6 trans-signaling: the heat is on.
    Immunity. 2004 Jan;20(1):2-4 PMID: 14738759
  17. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7.
    J Immunol. 2004 May 1;172(9):5149-53 PMID: 15100250
  18. Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity.
    Nat Immunol. 2004 Nov;5(11):1149-56 PMID: 15448689
  19. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma.
    N Engl J Med. 1992 Jan 30;326(5):298-304 PMID: 1530827
  20. Cytokines in symptomatic asthma airways.
    J Allergy Clin Immunol. 1992 May;89(5):958-67 PMID: 1374772
  21. International consensus report on diagnosis and treatment of asthma. National Heart, Lung, and Blood Institute, National Institutes of Health. Bethesda, Maryland 20892. Publication no. 92-3091, March 1992.
    Eur Respir J. 1992 May;5(5):601-41 PMID: 1612163
  22. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma.
    J Allergy Clin Immunol. 1993 Aug;92(2):313-24 PMID: 8349942
  23. T cells are the principal source of interleukin-5 mRNA in allergen-induced rhinitis.
    Am J Respir Cell Mol Biol. 1993 Oct;9(4):356-60 PMID: 8398174
  24. Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice.
    Nat Genet. 1995 Oct;11(2):150-4 PMID: 7550342
  25. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line.
    Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3963-6 PMID: 8632998
  26. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis.
    Immunity. 1996 Nov;5(5):449-60 PMID: 8934572
  27. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells.
    J Exp Med. 1997 Feb 3;185(3):461-9 PMID: 9053446
  28. IL-5 production by bronchoalveolar lavage and peripheral blood mononuclear cells in asthma and atopy.
    Eur Respir J. 1997 Mar;10(3):624-32 PMID: 9072996
  29. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment.
    Immunity. 1997 Mar;6(3):315-25 PMID: 9075932
  30. T-lymphocytes regulate genetically determined airway hyperresponsiveness in mice.
    Nat Med. 1997 Apr;3(4):460-2 PMID: 9095183
  31. IL-6 rescues resting mouse T cells from apoptosis.
    J Immunol. 1997 Jun 15;158(12):5791-6 PMID: 9190930
  32. Circulating levels of soluble interleukin-6 receptor in patients with bronchial asthma.
    Am J Respir Crit Care Med. 1997 Nov;156(5):1688-91 PMID: 9372694
  33. Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.
    J Clin Invest. 1997 Dec 15;100(12):3083-92 PMID: 9399955
  34. Soluble receptors for cytokines and growth factors: generation and biological function.
    Biochem J. 1994 Jun 1;300 ( Pt 2):281-90 PMID: 8002928
  35. Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3.
    Immunity. 1999 Oct;11(4):473-82 PMID: 10549629
  36. The epidemic of allergy and asthma.
    Nature. 1999 Nov 25;402(6760 Suppl):B2-4 PMID: 10586888
  37. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.
    Nat Med. 2000 May;6(5):583-8 PMID: 10802717
  38. The soluble interleukin 6 receptor: mechanisms of production and implications in disease.
    FASEB J. 2001 Jan;15(1):43-58 PMID: 11149892
  39. Structure of an extracellular gp130 cytokine receptor signaling complex.
    Science. 2001 Mar 16;291(5511):2150-5 PMID: 11251120
  40. Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression.
    J Exp Med. 2001 Jun 4;193(11):1247-60 PMID: 11390432
  41. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation.
    Immunity. 2001 Jun;14(6):705-14 PMID: 11420041
  42. Sequential activation of Rac-1, SEK-1/MKK-4, and protein kinase Cdelta is required for interleukin-6-induced STAT3 Ser-727 phosphorylation and transactivation.
    J Biol Chem. 2001 Jul 20;276(29):27709-15 PMID: 11335711
  43. Cytokine profile of bronchoalveolar lavage-derived CD4(+), CD8(+), and gammadelta T cells in people with asthma after segmental allergen challenge.
    Am J Respir Cell Mol Biol. 2001 Jul;25(1):125-31 PMID: 11472985
  44. Regulatory T cells in the control of immune pathology.
    Nat Immunol. 2001 Sep;2(9):816-22 PMID: 11526392
  45. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology.
    J Clin Invest. 2002 Jan;109(1):29-39 PMID: 11781348
  46. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet.
    Science. 2002 Jan 11;295(5553):336-8 PMID: 11786643
  47. The role of Th1/Th2 polarization in mucosal immunity.
    Nat Med. 2002 Jun;8(6):567-73 PMID: 12042806
  48. Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation.
    J Exp Med. 2002 Jul 1;196(1):39-49 PMID: 12093869
  49. The paradigm of IL-6: from basic science to medicine.
    Arthritis Res. 2002;4 Suppl 3:S233-42 PMID: 12110143
  50. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity.
    Nat Med. 2002 Sep;8(9):1024-32 PMID: 12145647
  51. The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases.
    Biochim Biophys Acta. 2002 Nov 11;1592(3):323-43 PMID: 12421676
  52. IL-6-regulated transcription factors.
    Int J Biochem Cell Biol. 1997 Dec;29(12):1401-18 PMID: 9570135
  53. Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis.
    Blood. 1998 Nov 15;92(10):3495-504 PMID: 9808540
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI22433
Published
2005-02-00
Pages
313-25
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC544603
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1172/JCI22433 PMC Full Text View journal details
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