Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells

• Published in: International immunology Vol. 19; no. 6; pp. 685 - 693
• Main Authors: Finotto, Susetta, Eigenbrod, Tatjana, Karwot, Roman, Boross, Ildiko, Doganci, Aysefa, Ito, Hiroaki, Nishimoto, Norihiro, Yoshizaki, Kazuyuki, Kishimoto, Tadamitsu, Rose-John, Stefan, Galle, Peter R., Neurath, Markus F.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.06.2007; Oxford Publishing Limited (England)
• Subjects: allergic asthma; Animals; Antibodies - immunology; Antibodies - pharmacology; Apoptosis - drug effects; Apoptosis - immunology; Asthma; Asthma - immunology; Bronchoalveolar Lavage Fluid - cytology; Bronchoalveolar Lavage Fluid - immunology; CD4+CD25+ T regulatory cells; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Coculture Techniques; Cytokine Receptor gp130 - genetics; Disease Models, Animal; Female; Forkhead Transcription Factors - genetics; Gene Expression; IL-6R; Immunization; Immunoglobulin Fc Fragments - genetics; Interleukin-6 - pharmacology; lung; Lung - immunology; Lung - metabolism; Lung - pathology; Mice; Mice, Inbred BALB C; Ovalbumin - immunology; Phosphorylation - drug effects; Receptors, Interleukin-6 - immunology; Recombinant Fusion Proteins - pharmacology; Signal Transduction - drug effects; Signal Transduction - immunology; STAT-1; STAT-3; STAT3 Transcription Factor - metabolism; T cell apoptosis; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Transducers; lung; IL-6R; allergic asthma; T cell apoptosis; STAT-1; STAT-3; CD4+CD25+ T regulatory cells
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxm037

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 (αIL-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 αIL-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.