IL-13 regulates Th17 secretion of IL-17A in an IL-10-dependent manner.
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.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. dawn.newcomb@vanderbilt.edu
Dawn C
DC
Newcomb
Madison G
MG
Boswell
Matthew M
MM
Huckabee
Kasia
K
Goleniewska
Daniel E
DE
Dulek
Sara
S
Reiss
Nicholas W
NW
Lukacs
Jay K
JK
Kolls
R Stokes
RS
Peebles
D000818:Animals; D002465:Cell Movement; D016753:Interleukin-10 / Q000502:physiology*; D018793:Interleukin-13 / Q000502:physiology*; D020381:Interleukin-17 / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000473:pathology / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology; D058504:Th17 Cells / Q000378:metabolism*
C556062:IL10 protein, mouse; D018793:Interleukin-13; D020381:Interleukin-17; D016753:Interleukin-10