101. The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo
- Author
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Doganci, A., Eigenbrod, T., Krug, N., De Sanctis, G. T., Hausding, M., Erpenbeck, V. J., Haddad, e., Lehr, H. A., Schmitt, E., Bopp, T., Kallen, K. J., Herz, U., Schmitt, S., Luft, C., Hecht, O., Hohlfeld, J. M., Ito, H., Nishimoto, N., Yoshizaki, K., Kishimoto, T., Rose-John, S., Renz, H., Neurath, M. F., Galle, P. R., Finotto, S., and Publica
- Subjects
Adult ,Male ,STAT3 Transcription Factor ,Ovalbumin ,Article ,Antibodies ,Mice ,Th2 Cells ,immune system diseases ,Hypersensitivity ,Animals ,Humans ,Receptors, Cytokine ,Lung ,Homeodomain Proteins ,Inflammation ,Mice, Knockout ,Forkhead Transcription Factors ,Receptors, Interleukin-2 ,General Medicine ,Receptors, Interleukin-6 ,Asthma ,Adult/Animals/Antibodies/administration & dosage/immunology/Asthma/Pathology/DNA-Binding Proteins/Female/Forkhead Transcription Factors/Homeodomain Proteins/genetics/Humans/Hypersensitivity/Inflammation/Lung/Male/Mice/Mice,Knockout/Ovalbumin/metabolism/Receptors,Cytokine/Receptors,Interleukin-2/Receptors,Interleukin-6/STAT3 Transcription Factor/Signal Transduction/drug effects/Th2 Cells/Trans-Activators ,DNA-Binding Proteins ,Trans-Activators ,Female ,Corrigendum ,Signal Transduction - 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.
- Published
- 2005