Reviews and feature articleIL-13 in asthma and allergic disease: Asthma phenotypes and targeted therapies
Section snippets
IL-13/IL-4 pathway in asthma
Allergic asthma is the most common and well-characterized manifestation of the syndrome. The immune response to allergen exposure in the asthmatic airway is complex and involves many cell types. These processes have been reviewed elsewhere.6, 7 As stated above, abundant evidence has shown that IL-13 directs many of the processes involved in the allergic asthmatic response (Fig 1). In the current model of allergic airway inflammation, inhaled allergen initiates activation of mast cells. TH2
Asthma pathobiology and associated heterogeneity
Despite the considerable body of knowledge that has accumulated regarding the role of IL-13 in allergic asthma, asthma is a chronic inflammatory disease that presents in patients with marked heterogeneity in regard to severity, responses to medications, symptoms, and disease management. Thus, not all pathways active in human asthma are IL-13 driven. In addition, the current clinical guidelines for asthma diagnosis and management do not recognize that different phenotypes of asthma exist that
Asthma subphenotypes
Recognizing the inherent heterogeneity within asthma and the benefits of classifying asthma by phenotype to potentially target asthma therapy, several groups have used multivariate approaches to define clusters or clinical phenotypes of asthma.80, 81 The studies used cluster analyses to identify similarities between patients based on multiple specified variables and then group the patients into clusters that would support the similarities of patients in the same cluster and distinguish patients
TH2 signature and use of biomarkers to phenotype asthma
A different approach for defining subphenotypes of asthma is to use knowledge of molecular pathways to distinguish patient subsets based on distinct inflammatory phenotypes. An elegant study was conducted by Woodruff et al86 in which a 3-gene signature composed of periostin (POSTN), chloride-channel regulator 1 (CLCA1), and serpin peptidase inhibitor clade B, member 2 (SERPINB2), in airway epithelial cells was used as a surrogate marker of TH2 inflammation. In a cohort of 70 subjects, 42
Asthma phenotypes and response to TH2 cytokine inhibition
Phenotyping human asthma has demonstrated that approximately 50% of asthmatic patients demonstrate a TH2-driven phenotype.86 Therefore therapies that target this type of inflammation will not be uniformly effective in asthmatic patients. Recently, an innovative study was conducted to prove the efficacy of lebrikizumab (Genentech, San Francisco, Calif), a humanized mAb that specifically binds to and inhibits the activity of IL-13, in patients with uncontrolled asthma.106 This study was unique in
Specifically targeting the IL-13 pathway in asthmatic patients
In addition to the Corren et al106 study, several approaches have been used to target IL-13, IL-13/IL-4 receptors, and STAT6 in clinical trials of both acute and chronic asthma. These approaches include an IL-4 variant, mAbs to IL-4Rα or IL-13, or inhibitory RNAs and peptides specific for STAT6. The results gathered from these studies significantly contribute to our understanding of the roles of IL-13 and its receptors in the pathobiology of human asthma.
First, 2 groups performed clinical
Conclusions
Strong experimental evidence has accumulated over the years to demonstrate that IL-13 directs many of the important features of airway inflammation and remodeling in patients with allergic asthma. Yet an almost equally rich body of evidence has shown that asthma is a complex heterogeneous disease characterized by different severities, cellular inflammation subtypes, and molecular subphenotypes. Biomarkers have now been identified that correlate IL-13 expression and airway inflammation in
References (153)
Asthma and allergic inflammation
Cell
(2010)- et al.
Mast cells produce interleukin-25 upon Fc epsilon RI-mediated activation
Blood
(2003) - et al.
IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism
J Allergy Clin Immunol
(2001) - et al.
The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1 (IL13Ralpha1)
J Biol Chem
(2011) - et al.
Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system
Cell
(2008) - et al.
STAT-1 is activated by IL-4 and IL-13 in multiple cell types
Mol Immunol
(2004) - et al.
Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling
J Biol Chem
(2006) - et al.
Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain
J Biol Chem
(1996) - et al.
IL-13 receptor alpha 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts
J Allergy Clin Immunol
(2006) - et al.
Increased interleukin-13 mRNA expression in bronchoalveolar lavage cells of atopic patients with mild asthma after repeated low-dose allergen provocations
Respir Med
(2000)
IL-4, IL-13, and dexamethasone augment fibroblast proliferation in asthma
J Allergy Clin Immunol
Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals
J Allergy Clin Immunol
Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma
Am J Hum Genet
Smoking and asthma: clinical and radiologic features, lung function, and airway inflammation
Chest
Neutrophilic inflammation is associated with altered airway hydration in stable asthmatics
Respir Med
Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial
Lancet
Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years
J Allergy Clin Immunol
Fraction of exhaled nitric oxide at 50 mL/s: reference values for adult lifelong never-smokers
Chest
Interleukin-13: central mediator of allergic asthma
Science
Requirement for IL-13 independently of IL-4 in experimental asthma
Science
Interleukin 13 and interleukin 4 receptor-alpha polymorphisms in rhinitis and asthma
Int Arch Allergy Immunol
Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma
Curr Mol Med
Interleukin-13: prospects for new treatments
Clin Exp Allergy
Asthma phenotypes and interleukin-13—moving closer to personalized medicine
N Engl J Med
The role of IL-13 in IgE synthesis by allergic asthma patients
Clin Exp Immunol
IL-33-activated dendritic cells are critical for allergic airway inflammation
Eur J Immunol
IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells
Int Immunol
IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells
J Exp Med
IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs
J Immunol
Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161
Nat Immunol
Th2 cytokines IL-4 and IL-13 downregulate paxillin expression in bronchial airway epithelial cells
J Clin Immunol
Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production
J Clin Invest
IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells
Clin Exp Allergy
Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma
Nat Med
Transcriptional regulation by STAT6
Immunol Res
Opposing actions of Stat1 and Stat6 on IL-13-induced up-regulation of early growth response-1 and platelet-derived growth factor ligands in pulmonary fibroblasts
J Immunol
Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension
Am J Respir Crit Care Med
IL-13R alpha 2 membrane and soluble isoforms differ in humans and mice
J Immunol
A novel and sensitive ELISA reveals that the soluble form of IL-13R-alpha2 is not expressed in plasma of healthy or asthmatic subjects
Clin Exp Allergy
The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1
J Immunol
IL-13 receptor alpha2 selectively inhibits IL-13-induced responses in the murine lung
J Immunol
Airway fibroblasts in asthma manifest an invasive phenotype
Am J Respir Crit Care Med
IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis
Nat Med
Elevated IL-13Ralpha2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway
Inflamm Bowel Dis
A novel role of interleukin-13 receptor alpha2 in pancreatic cancer invasion and metastasis
Cancer Res
Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1)
J Exp Med
IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells
Int Immunol
IL-13 expression at the sites of allergen challenge in patients with asthma
J Immunol
Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells
J Immunol
The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma
Am J Respir Cell Mol Biol
Cited by (217)
Fenofibrate attenuates asthma features in an ovalbumin-induced mouse model via suppressing NF-κB binding activity
2023, Respiratory Physiology and NeurobiologyPediatric obesity and severe asthma: Targeting pathways driving inflammation
2023, Pharmacological ResearchAllergen immunotherapy for allergic airway diseases: Use lessons from the past to design a brighter future
2022, Pharmacology and TherapeuticsMetabolomics in asthma: A platform for discovery
2022, Molecular Aspects of MedicineEffect of polycyclic aromatic hydrocarbons on immunity
2022, Journal of Translational Autoimmunity
Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD