title: Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells.
abstract: 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 (alphaIL-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 alphaIL-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.
authors.affiliation: Laboratory of Cellular and Molecular Immunology of the Lung, First Medical Clinic, University of Mainz, Germany. finotto@mail.uni-mainz.de
authors.forename: Susetta
authors.initials: S
authors.lastname: Finotto
authors.forename: Tatjana
authors.initials: T
authors.lastname: Eigenbrod
authors.forename: Roman
authors.initials: R
authors.lastname: Karwot
authors.forename: Ildiko
authors.initials: I
authors.lastname: Boross
authors.forename: Aysefa
authors.initials: A
authors.lastname: Doganci
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ito
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishimoto
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yoshizaki
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018920:Coculture Techniques; D050822:Cytokine Receptor gp130 / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression; D007114:Immunization; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D000906:Antibodies; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C494200:Il6st protein, mouse; D007141:Immunoglobulin Fc Fragments; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; D010047:Ovalbumin