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

Abstract

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.

RIG-like Helicase Innate Immunity Inhibits Vascular Endothelial Growth Factor Tissue Responses via a Type I IFN–dependent Mechanism

“…This led us to determine whether poly(I:C) also inhibited aeroallergen-induced Th2 inflammation. As previously described by our laboratory and others (41,42), ovalbumin (OVA) sensitization and challenge increased BAL and tissue total cell, macrophage, eosinophil, and lymphocyte recovery ( Figures 12A212D and data not shown). In all cases these inductive effects were abrogated by treatment with poly(I:C) ( Figures 12A212D and data not shown).…”

“…Levels of MUC5AC, the major airway mucin in BAL fluids, were assessed as previously described (41). In these evaluations, 0.1 ml of 1:100 diluted BAL fluid was slot-blotted onto nitrocellulose membranes, using a Minifold II slot-blot apparatus (Schleicher and Schuell, Keene, NH).…”

“…Ovalbumin (OVA) sensitization (with alum) and aerosol OVA challenge were undertaken as previously described by our laboratories (41,42). Responses of mice that had been treated with poly(I:C) or vehicle 24 hours before aerosol challenge were compared.…”

Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions

“…An IL-11 antagonist with a higher potency was obtained based on the W167A mutation by screening targeted libraries for variants with increased affinity for IL-11Ra [30]. It is a variant of mouse IL-11 that contains five continuous substitutions at positions 79-83 (AMSAG ?…”

Non-core Region Modulates Interleukin-11 Signaling Activity

“…This variant of hIL-11 (and other analogous variants with L A/B -O-like properties) could be employed, for example, to ameliorate pathologies that involve endogenously hyperactive interleukin-11 such as in certain classes of inflammation (43), or in conditions where receptor hIL-11R is overexpressed such as in bone metastasis (44). However, further experimentation will be needed before these novel medications can be put into practice.…”