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- Dawn C. Newcomb
- *Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
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- Madison G. Boswell
- *Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
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- Matthew M. Huckabee
- *Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
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- Kasia Goleniewska
- *Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
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- Daniel E. Dulek
- †Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232;
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- Sara Reiss
- *Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
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- Nicholas W. Lukacs
- ‡Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
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- Jay K. Kolls
- §Department of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213
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- R. Stokes Peebles
- *Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
説明
<jats:title>Abstract</jats:title> <jats:p>IL-13 is a central mediator of airway hyperresponsiveness and mucus expression, both hallmarks of asthma. IL-13 is found in the sputum of patients with asthma; therefore, IL-13 is an attractive drug target for treating asthma. We have shown previously that IL-13 inhibits Th17 cell production of IL-17A and IL-21 in vitro. Th17 cells are associated with autoimmune diseases, host immune responses, and severe asthma. In this study, we extend our in vitro findings and determine that IL-13 increases IL-10 production from Th17-polarized cells and that IL-13–induced IL-10 production negatively regulates the secretion of IL-17A and IL-21. To determine if IL-13 negatively regulates lung IL-17A expression via an IL-10–dependent mechanism in vivo, we used a model of respiratory syncytial virus (RSV) strain A2 infection in STAT1 knockout (KO) mice that increases lung IL-17A and IL-13 expression, cytokines not produced during RSV infection in wild-type mice. To test the hypothesis that IL-13 negatively regulates lung IL-17A expression, we created STAT1/IL-13 double KO (DKO) mice. We found that RSV-infected STAT1/IL-13 DKO mice had significantly greater lung IL-17A expression compared with that of STAT1 KO mice and that increased IL-17A expression was abrogated by anti-IL-10 Ab treatment. RSV-infected STAT1/IL-13 DKO mice also had increased neutrophil infiltration compared with that of RSV-infected STAT1 KO mice. Neutralizing IL-10 increased the infiltration of inflammatory cells into the lungs of STAT1 KO mice but not STAT1/IL-13 DKO mice. These findings are vital to understanding the potential side effects of therapeutics targeting IL-13. Inhibiting IL-13 may decrease IL-10 production and increase IL-17A production, thus potentiating IL-17A–associated diseases.</jats:p>
収録刊行物
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- The Journal of Immunology
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The Journal of Immunology 188 (3), 1027-1035, 2012-02-01
The American Association of Immunologists