IL-13 as a therapeutic target for respiratory disease

doi:10.1016/j.bcp.2008.04.002

Biochemical Pharmacology

Volume 76, Issue 2, 15 July 2008, Pages 147-155

https://doi.org/10.1016/j.bcp.2008.04.002 Get rights and content

Abstract

Interleukin-13 (IL-13) is a critical mediator of asthma pathology. On B cells, monocytes, epithelial cells, and smooth muscle cells, IL-13 acts through the IL-13Rα1/IL-4Rα complex to directly induce activation responses that contribute to atopic disease. In human populations, genetic polymorphisms in IL-13, its receptor components, or the essential signaling element STAT6, have all been associated with increased risk of atopy and asthma. Animal studies using IL-13 deficient mice, IL-13 transgenic animals, and IL-13 neutralization strategies have confirmed an essential role for this cytokine in driving major correlates of asthma pathology, including airway hyperresponsiveness (AHR), lung eosinophilia, mucus generation, and fibrosis. Ongoing studies continue to define both overlapping and distinct roles for IL-13 and the related cytokine, IL-4, in promoting asthmatic changes. Furthermore, new evidence concerning the role of the “decoy” receptor, IL-13Rα2, has prompted re-evaluation of the receptor forms that underlie the numerous activities of IL-13. In this review, we summarize the essential role of IL-13 in asthma, compare the relative contributions of IL-13 and IL-4 to key aspects of the asthmatic phenotype, and outline novel therapeutic strategies to target this critical cytokine.

Introduction

IL-13 is a Th2 cytokine that has emerged as a critical regulator of inflammatory immune responses, with key roles in asthma and parasite immunity [1], [2]. In vitro, IL-13 drives many cellular responses relevant to asthma, including epithelial cell maturation and mucus production, generation of extracellular matrix proteins, and enhanced contractility of airway smooth muscle cells [2]. Generated by activated Th2 cells, NKT cells, mast cells, and basophils, IL-13 shares approximately 20% amino acid sequence identity, and a range of cellular activities, with IL-4 [1], [3]. Both IL-4 and IL-13 were originally described based on their ability to promote IgE switch recombination, and remain the only cytokines known to possess this activity. The genes encoding both cytokines are localized within the cytokine gene cluster on human chromosome 5q31 [4], which also includes the genes encoding IL-5 and IL-3. The common activities of IL-13 and IL-4 are mediated through the IL-4Rα/IL-13Rα1 receptor complex shared by both cytokines. Because IL-4 may also utilize the IL-4Rα/γ common receptor complex, it has additional activities which are not shared by IL-13, including effects on T cell maturation and skewing to Th2 [3].

A wealth of data supports a role for IL-13 in mediating asthma pathology. IL-13 can be detected in the bronchial tissue [5], nasal lavage fluid [6], and induced sputum [5] of asthmatics. Following segmental allergen challenge, bronchoalveolar lavage (BAL) fluid contains IL-13 mRNA [7] and IL-13 protein [8], confirming that the cytokine is generated in the lung in response to respiratory provocation. Similar observations have been noted in animal models. In mice immunized and given lung challenge with ovalbumin or house dust mite, significant increases in IL-13 mRNA and protein can be found in lung tissue and BAL fluid [9].

Numerous additional findings demonstrate a role for IL-13 in mediating pathology in the lung. Pulmonary delivery of IL-13 to mice [10], [11], [12] or targeted overexpression of IL-13 to the lung [13], [14] induces multiple correlates of asthma pathology, including airway eosinophilia, mucus cell metaplasia, airway fibrosis, eotaxin production, and AHR. Despite their shared activities, studies in animal models have pointed to a preferential role for IL-13 over IL-4 in driving asthma pathology [11], [15]. In the following sections, we will explore the evidence, summarized in Table 1, linking IL-13 to key disease parameters. In addition, we will review IL-13 receptor interactions, and summarize ongoing strategies to target IL-13, IL-4, or both for the treatment of asthma.

Section snippets

Airway hyperresponsiveness and inflammation

Both IL-4 and IL-13 contribute to AHR and inflammation in animal models. Initial observations demonstrated that pulmonary delivery of IL-4 induces AHR and mucus production in mice, but not airway inflammation [11], [16], [17]. Paradoxically, animals with IL-4 transgenically targeted to the lung developed airway inflammation, mucus, and high serum IgE, but not AHR [18], [19]. IL-4-deficient mice were protected from airway eosinophilia, and exhibited reduced bronchial hyperresponsiveness [20].

Mucus production

Mucus generation responses are impaired in mice lacking IL-13, but not in those lacking IL-4 [23], [30]. This activity could be critical for promoting asthma pathology, as IL-13 responsiveness restricted to epithelial cells appears sufficient to drive AHR and mucus production [12]. The molecular basis for the greater dependence of mucus production on IL-13 over IL-4 remains to be determined. In human bronchial epithelial cells, both cytokines increase goblet cell density, mucin gene expression,

Fibrosis

IL-13 also appears more critical than IL-4 in driving fibrotic responses in vivo[1]. In models of murine lung fibrosis induced by bleomycin or FITC, IL-4 has proved to be non-essential [34], whereas IL-13-deficient animals were protected from fibrotic changes [35], [36]. In an inducible model of transgenic lung IL-13 expression, fibrosis was initiated upon IL-13 induction and persisted even following withdrawal of the cytokine, demonstrating that IL-13 has the capacity to drive irreversible

IL-13Rα1/IL-4Rα binding and signaling interactions

IL-13 bioactivity is mediated through a receptor complex consisting of IL-13Rα1 and IL-4Rα chains. Of the four alpha helices that comprise IL-13, the C-terminal alpha helix D contains key residues for interaction with both IL-13Rα1 and IL-13Rα2, whereas helices A and C appear primarily responsible for IL-13 interaction with IL-4Rα[49], [50]. Recently, crystal structures of ternary complexes consisting of IL-4 or IL-13 interacting with IL-13Rα1 and IL-4Rα chains have been solved [51]. Analysis

IL-13 interactions with IL-13Rα2

IL-13Rα2 is inducibly expressed on fibroblasts, keratinocytes, epithelial cells, macrophages, and certain tumor cells, and binds IL-13 with high affinity (∼10⁻¹¹ M) [45], [60]. Although it has been proposed to mediate AP-1-dependent signaling responses under certain activation conditions [43], IL-13Rα2 is thought to act primarily as a “decoy” receptor, sequestering IL-13 from the IL-13Rα1/IL-4Rα complex, and thus inhibiting its function [44]. Cell surface IL-13Rα2 is normally absent on resting

Genetic associations with human asthma

Several IL-13 genetic polymorphisms have been linked with susceptibility to develop atopic disease. In populations throughout the world, the R110Q variant has been associated with high serum IgE titers, allergy, and atopic dermatits [72], [73]. Residue #110 of IL-13 lies in the region of the molecule thought to interact with IL-13Rα1 and IL-13Rα2 [50]. Several hypotheses have been proposed to rationalize the association of this polymorphic variant IL-13 with tendency to develop atopic disease,

Therapeutic strategies targeting both IL-13 and IL-4

Despite the wealth of preclinical data validating the importance of IL-4 and IL-13 in asthma models, the pathway has been difficult to effectively target therapeutically. One promising strategy has taken advantage of the finding that a single amino acid mutation, Y124D, converts human IL-4 to a potent IL-4 antagonist [76], and a double mutant, R121D/Y124D, blocks all signaling responses through IL-4Rα[77]. By binding to the IL-4Rα without apparent signaling capacity, these mutants inhibit

Therapeutic strategies targeting IL-4

Antibody to IL-4 initially appeared to be a promising strategy for treatment of asthma. In preclinical testing, monoclonal anti-IL-4 blocked development of specific IgE and AHR to ovalbumin in mice, but did not abrogate eosinophilia [84]. Humanized antibody to IL-4 (pascolizumab) effectively blocked IL-4 responses in vitro, and showed a favorable in vivo pharmacokinetic profile in cynomolgus monkeys [85]. Nevertheless, phase II testing in steroid-naïve asthmatics showed no apparent clinical

Therapeutic strategies targeting IL-13

In murine systems, IL-13 blockade by sIL-13Rα2-Fc [10], [11] or by antibody [91] effectively limits asthmatic responses, including AHR, eosinophilia, mucus production, IgE generation, and fibrosis. A number of monoclonal antibodies targeting IL-13 are being developed for the treatment of asthma, with several more in preclinical development. Results of clinical studies are not yet available, but preclinical data indicates a promising therapeutic profile. In mice, AHR, airway eosinophilia, and

Conclusion

IL-13 neutralization by sIL-13Rα2-Fc [10], [11], [48], siRNA [98], or antibody [91], [93], [94], [95] effectively blocks signs of asthma pathology, including airway hyperresponsiveness, lung inflammation, mucus production, fibrosis and increased serum IgE, in murine, NHP, and sheep models of respiratory disease. IL-13 has been described as “necessary and sufficient” for development of allergic asthma in animal models [10], [12], [15]. Several strategies are currently being investigated to

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CommentaryIL-13 as a therapeutic target for respiratory disease

Abstract

Introduction

Section snippets

Airway hyperresponsiveness and inflammation

Mucus production

Fibrosis

IL-13Rα1/IL-4Rα binding and signaling interactions

IL-13 interactions with IL-13Rα2

Genetic associations with human asthma

Therapeutic strategies targeting both IL-13 and IL-4

Therapeutic strategies targeting IL-4

Therapeutic strategies targeting IL-13

Conclusion

Immunol Today

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Pathol

Biochem Biophys Res Commun

J Allergy Clin Immunol

J Mol Biol

J Biol Chem

Cell

J Biol Chem

J Allergy Clin Immunol

Lab Invest

J Biol Chem

Blood

J Allergy Clin Immunol

Biochem Biophys Res Commun

J Allergy Clin Immunol

J Biol Chem

Lancet

Immunol Allergy Clin North Am

J Allergy Clin Immunol

Cytokine

J Allergy Clin Immunol

Cytokine Growth Factor Rev

IL-13 effector functions

Annu Rev Immunol

Interleukin-13 in asthma pathogenesis

Immunol Rev

The gene encoding interleukin-13: a susceptibility locus for asthma and related traits

Respir Res

Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-beta1, TGF-beta2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on alpha-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts

Clin Exp Allergy

Interleukin-13: central mediator of allergic asthma

Science

Requirement for IL-13 independently of IL-4 in experimental asthma

Science

Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma

Nat Med

Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production

J Clin Invest

IL-13 overexpression predisposes to anaphylaxis following antigen sensitisation

J Immunol

Critical role for IL-13 in the development of allergen-induced airway hyperreactivity

J Immunol

The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells

Am J Respir Cell Mol Biol

IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo

J Immunol

Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity

Proc Natl Acad Sci USA

Humoral immune functions in IL-4 transgenic mice

J Immunol

Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice

Am J Respir Cell Mol Biol

Aeroallergen-induced eosinophilic inflammation, lung damage, and airways hyperreactivity in mice can occur independently of IL-4 and allergen-specific immunoglobulins

J Clin Invest

A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5

J Immunol

Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity

J Immunol

Polymorphisms in IL-4R alpha correlate with airways hyperreactivity, eosinophilia, and Ym protein expression in allergic IL-13−/− mice

J Immunol

IgE generation and mast cell effector function in mice deficient in IL-4 and IL-13

Commentary
IL-13 as a therapeutic target for respiratory disease