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

• DOI: 10.1165/rcmb.2008-0053oc
• Publication Date: 2008-07-11T01:43:46Z
• Authors: Chun Geun Lee; Dominik Hartl; Hiroshi Matsuura; Felicity M. Dunlop; Pierre D. Scotney; Louis J. Fabri; Andrew D. Nash; Ning-Yuan Chen; Chu-Yan Tang; Qingsheng Chen; Robert J. Homer; Manuel Baca; Jack A. Elias
• Keywords: Inflammation; 0301 basic medicine; Interleukin-13; Ovalbumin; Tumor Necrosis Factor-alpha; Cell Count; Allergens; Mucin 5AC; Interleukin-11; 3. Good health; Mice, Inbred C57BL; Mice; Mucus; 03 medical and health sciences; Phenotype; Th2 Cells; Gene Expression Regulation; Animals; Receptors, Interleukin-11; Immunization; Bronchoalveolar Lavage Fluid; Signal Transduction

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.