International Immunology Advance Access originally published online on May 11, 2007
International Immunology 2007 19(6):685-693; doi:10.1093/intimm/dxm037
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Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells
1 Laboratory of Cellular and Molecular Immunology of the Lung, First Medical Clinic, University of Mainz, Germany
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan
3 Institute of Biochemistry, University of Kiel, Germany
4 Laboratory of Immunology, First Medical Clinic, University of Mainz, Germany
Correspondence to: S. Finotto; E-mail: finotto{at}mail.uni-mainz.de
We previously reported high levels of the soluble form of the IL-6R (sIL-6R) in the airways of asthmatic subjects. Here, we analyzed the IL-6R effects on Th2 cell survival in the lung by locally antagonizing sIL-6R-mediated trans-signaling with a designer fusion protein (gp130-Fc) as well as IL-6R signaling with an antibody against the gp80 unit of the IL-6R (
IL-6R) in a murine model of asthma after ovalbumin peptide (OVA) sensitization and challenge. Blockade of the sIL-6R led to a significant decrease in inflammatory cells by an apoptosis-independent mechanism. In contrast, local treatment with IL-6R antibodies that also block signaling via the membrane-bound IL-6R (mIL-6R) led to decreased signal transducers and activators of transcription (STAT)-3 but not STAT-1 phosphorylation in the lung of treated mice as compared with control-treated mice. Moreover, this treatment induced apoptosis of the cells present in the airways of OVA-treated mice as well as apoptosis of lung CD4+ effector T cells. Subsequent studies showed that this effect was mediated by lung CD4+CD25+Foxp3+ T regulatory cells by a cell–cell interaction, thereby contributing to the resolution of airway hyperresponsiveness in OVA-treated mice given anti-IL-6R antibodies. Taken together, these data suggest that blockade of mIL-6R signaling leads to cell death of lung effector T cells by activating regulatory T cells in experimental asthma. Local targeting of IL-6R signaling could be a novel approach for inducing Th2 T cell death in allergic airways via regulatory T cells.
Keywords: allergic asthma, CD4+CD25+ T regulatory cells, IL-6R, lung, STAT-1, STAT-3, T cell apoptosis
* These authors contributed equally to this study.
Received 24 November 2006, accepted 7 March 2007.
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