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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.

Authors: Finotto, S  Eigenbrod, T  Karwot, R  Boross, I  Doganci, A  Ito, H  Nishimoto, N  Yoshizaki, K  Kishimoto, T  Rose-John, S  Galle, PR  Neurath, MF 
Citation: Finotto S, etal., Int Immunol. 2007 Jun;19(6):685-93. Epub 2007 May 11.
Pubmed: (View Article at PubMed) PMID:17496315
DOI: Full-text: 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 (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.

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CRRD Object Information
CRRD ID: 5128662
Created: 2011-03-15
Species: All species
Last Modified: 2011-03-15
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.