IL-13 Regulates Th17 Secretion of IL-17A in an IL-10–Dependent Manner
Open Access
- 1 February 2012
- journal article
- Published by The American Association of Immunologists
- Vol. 188 (3), 1027-1035
- https://doi.org/10.4049/jimmunol.1102216
Abstract
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.Keywords
This publication has 49 references indexed in Scilit:
- Th17 Cells Express Interleukin-10 Receptor and Are Controlled by Foxp3− and Foxp3+ Regulatory CD4+ T Cells in an Interleukin-10-Dependent MannerImmunity, 2011
- Colitis and Intestinal Inflammation in IL10−/− Mice Results From IL-13Rα2–Mediated Attenuation of IL-13 ActivityGastroenterology, 2011
- Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cellsEuropean Journal of Immunology, 2008
- The Biological Functions of T Helper 17 Cell Effector Cytokines in InflammationImmunity, 2008
- Cytokine Signaling Modules in Inflammatory ResponsesImmunity, 2008
- IL-22 mediates mucosal host defense against Gram-negative bacterial pneumoniaNature Medicine, 2008
- Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cellsNature Immunology, 2007
- A breath of hopeEMBO Reports, 2007
- IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infectionMicrobes and Infection, 2007
- IL-25 regulates Th17 function in autoimmune inflammationThe Journal of Experimental Medicine, 2007