Endogenous IL-11 signaling is essential in Th2- and IL-13-induced inflammation and mucus production.
IL-11 and IL-11 receptor (R)alpha are induced by Th2 cytokines. However, the role(s) of endogenous IL-11 in antigen-induced Th2 inflammation has not been fully defined. We hypothesized that IL-11, signaling via IL-11Ralpha, plays an important role in aeroallergen-induced Th2 inflammation and mucus metaplasia. To test this hypothesis, we compared the responses induced by the aeroallergen ovalbumin (OVA) in wild-type (WT) and IL-11Ralpha-null mutant mice. We also generated and defined the effects of an antagonistic IL-11 mutein on pulmonary Th2 responses. Increased levels of IgE, eosinophilic tissue and bronchoalveolar lavage (BAL) inflammation, IL-13 production, and increased mucus production and secretion were noted in OVA-sensitized and -challenged WT mice. These responses were at least partially IL-11 dependent because each was decreased in mice with null mutations of IL-11Ralpha. Importantly, the administration of the IL-11 mutein to OVA-sensitized mice before aerosol antigen challenge also caused a significant decrease in OVA-induced inflammation, mucus responses, and IL-13 production. Intraperitoneal administration of the mutein to lung-specific IL-13-overexpressing transgenic mice also reduced BAL inflammation and airway mucus elaboration. These studies demonstrate that endogenous IL-11R signaling plays an important role in antigen-induced sensitization, eosinophilic inflammation, and airway mucus production. They also demonstrate that Th2 and IL-13 responses can be regulated by interventions that manipulate IL-11 signaling in the murine lung.
Lee
Chun Geun
CG
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA. chungeun.lee@yale.edu
Hartl
Dominik
D
Matsuura
Hiroshi
H
Dunlop
Felicity M
FM
Scotney
Pierre D
PD
Fabri
Louis J
LJ
Nash
Andrew D
AD
Chen
Ning-Yuan
NY
Tang
Chu-Yan
CY
Chen
Qingsheng
Q
Homer
Robert J
RJ
Baca
Manuel
M
Elias
Jack A
JA
D000485:Allergens / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D007249:Inflammation / Q000378:metabolism*; D017370:Interleukin-11 / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology; D010641:Phenotype; D053702:Receptors, Interleukin-11 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000485:Allergens; D017370:Interleukin-11; D018793:Interleukin-13; D055271:Mucin 5AC; D053702:Receptors, Interleukin-11; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin