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

: Doganci, A.; Eigenbrod, T.; Krug, N.; Sanctis, G.T. de; Hausding, M.; Erpenbeck, V.J.; Haddad, E.-B.; 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.


Journal of clinical investigation 115 (2005), No.2, pp.313-325
ISSN: 0021-9738
Journal Article
Fraunhofer ITEM ()
forkhead transcription factor; homeodomain protein; ovalbumin; receptor, cytokine; Th2 cell; trans-activator; Asthma; DNA binding proteins; Hypersensitivity; Inflammation; Lungs; Mice; Signal transduction

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.