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Endogenous IL-11 Signaling Is Essential in Th2- and IL-13–Induced Inflammation and Mucus Production

¹ Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut; ² CSL Limited A.C.N., Parkville, Victoria, Australia; and ³ Department of Pathology, Yale University School of Medicine, and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut

Correspondence and requests for reprints should be addressed to Chun Geun Lee, M.D., Ph.D., Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 300 Cedar Street (S441 TAC), P.O. Box 208057, New Haven, CT 06520-8057. E-mail: chungeun.lee{at}yale.edu

IL-11 and IL-11 receptor (R) 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-11R, 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-11R–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-11R. 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.

Key Words: IL-11 • mutein • airway inflammation • mucus • IL-13

CLINICAL RELEVANCE This study is the first to demonstrate that endogenous IL-11 signaling is critical to Th2 aeroallergen- or IL-13–induced inflammation and airway mucus production.

 

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