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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