The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo
Aysefa Doganci, … , Peter R. Galle, Susetta Finotto
Aysefa Doganci, … , Peter R. Galle, Susetta Finotto
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):313-325. https://doi.org/10.1172/JCI22433.
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The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo

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 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.

Authors

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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Blockade of mIL-6R through i.n. application of anti–IL-6R antibodies ame...
Blockade of mIL-6R through i.n. application of anti–IL-6R antibodies ameliorates AHR and induces IFN-γ and IL-10 levels in BALF in a mouse model of asthma after OVA sensitization. (A) Eight to 10 BALB/c mice per group were sensitized to OVA-alum (OVA-sensitized mice) followed by local treatment with OVA alone or treatment with OVA plus either gp130-Fc, IgG, or anti–IL-6R antibody. Control mice were sensitized with saline-alum and exposed to saline aerosol (saline). Transpulmonary resistance was performed 24 hours after the last local treatment in all mice, as specified in Methods. Dose-response curves to MCh were obtained after administering indicated doses of intravenous MCh. OVA-sensitized mice reacted with an increase of airway resistance at low doses of MCh as compared to that of mice given saline. Anti–IL-6R–treated, OVA-sensitized mice were more protected from the development of AHR compared to untreated (P = 0.049) or IgG-treated, OVA-sensitized mice. Moreover, blockade of sIL-6R by gp130-Fc was less effective compared to anti–IL-6R antibody treatment. (B and C) Local anti–IL-6R antibody treatment induced significant release of IFN-γ (P = 0.048) (B) and IL-10 (P = 0.020) (C) in BALF of OVA-senstitized mice as compared to untreated, OVA-sensitized mice (5 < n < 15). Mean values ± SEM are shown. *P < 0.05.