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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 401-404, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.F264

Perspective

Interleukin-13 and Leukotrienes

An Intersection of Pathogenetic Schema

Jack A. Elias, Chun Geun Lee, Tao Zheng, Yun Shim and Zhou Zhu

Department of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut

Address correspondence to: Jack A. Elias, M.D., Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Department of Internal Medicine, 333 Cedar Street, 105 LCI, New Haven, CT 06520-8057. E-mail: jack.elias{at}yale.edu

Abbreviations: 5-lipoxygenase, 5-LO • arachidonic acid, AA • airway hyperresponsiveness, AHR • bronchoalveolar lavage, BAL • epidermal growth factor receptor, EGFR • interferon-{gamma}, IFN-{gamma} • immunoglobulin E, IgE • leukotriene, LT • matrix metalloproteinase, MMP • transforming growth factor, TGF • T helper, Th


   Introduction
Top
 Introduction
Th2 Cells and IL-13...
 Mechanisms of IL-13 Effector...
 Leukotrienes in Asthma
 The Intersection of IL-13...
 References
 
The episodic wheezing and shortness of breath caused by asthma has been recognized since antiquity. As a result, major efforts have been directed at studies of asthma pathogenesis. In the modern scientific era, these studies have caused an impressive evolution in our understanding of the processes that contribute to this disorder. A number of years ago, the airways dysfunction in asthma was viewed largely from the perspective of airways smooth muscle contraction (bronchospasm). It was assumed that an intrinsic abnormality in airway myocyte contractility was the cornerstone of the asthmatic diathesis. This was followed by the contention that asthma is a disease characterized by autonomic dysfunction with cholinergic and/or tachykinin excess, and then by the appreciation that IgE-mediated mast cell and/or basophil degranulation is a key event in the acute asthmatic response. Relatively recently studies using bronchoalveolar lavage (BAL) and bronchial biopsy demonstrated prominent eosinophil-, macrophage-, and lymphocyte-rich inflam-mation in asthmatic airways. When coupled with the well established clinical efficacy of steroids and the repeated demonstration of airway remodeling in the asthmatic airway, these findings led to the present-day concept that asthma is a chronic inflammatory disorder of the airway in which T helper (Th)2 cytokines such as interleukin (IL)-13 are pivotal effectors of inflammation and remodeling events that contribute to disease pathogenesis. Simultaneously, scientists discovered and characterized the leukotriene (LT) products of arachidonic acid (AA) metabolism and developed a variety of LT antagonists that were shown to be effective asthma therapeutics. This led to the widely held belief that LTs are also critical mediators in asthma pathogenesis. Surprisingly, however, the relationships between the cytokines that are central to the Th2 inflammation hypothesis, and the LT that are central to the lipid regulatory events in asthma, have not been extensively investigated. In this issue of the AJRCMB, Vargaftig and Singer address this gap in our knowledge and demonstrate, for the first time, that LTs play a critical role in IL-13 effector pathway activation (1). To put these observations into perspective, the importance of Th2 inflammation and IL-13, the mechanisms of IL-13 phenotype generation, and the role of LT in asthma are reviewed below.


   Th2 Cells and IL-13 in Asthma
Top
 Introduction
 Th2 Cells and IL-13...
Mechanisms of IL-13 Effector...
 Leukotrienes in Asthma
 The Intersection of IL-13...
 References
 
A major advance in our understanding of the immunopathogenesis of chronic inflammatory disorders such as asthma occurred when it was appreciated that the type of response that is generated by an antigen is influenced greatly by the types of T cells that accumulate at the site of local antigen deposition. This was most clearly demonstrated in the mouse, where a number of functionally distinct CD4 T cells have been defined based on the profile of the cytokines they elaborate. Th1 and Th2 cells have been the topic of the most intense study, with the former elaborating interferon (IFN)-{gamma}, IL-2, and lymphotoxin, and the latter elaborating IL-4, IL-5, IL-9, IL-13, and IL-10. Th1-polarized responses play a key role in macrophage activation and delayed-type hypersensitivity reactions. In contrast, Th2-dominant responses stimulate antibody-mediated responses, activate mast cells, elicit IgE production, and induce tissue eosinophilia. Th1-dominated responses are seen in a variety of diseases, including sarcoidosis and tuberculosis. In contrast, studies of biopsies and BAL from individuals with asthma have most often demonstrated enhanced production of Th2 cytokines including IL-4, IL-5, and IL-13 (2–4). In keeping with the importance of IgE and eosinophils, asthma is now looked at as a disease that is characterized by Th2 cell and Th2 cytokine excess (4, 5).

The appreciation that Th2 inflammation is the likely cornerstone of asthma pathogenesis quickly led to studies that were designed to define the contribution(s) of individual Th2 cytokines in this disorder. These studies demonstrated that IL-4 plays an important role in the early initiation phases of Th2 inflammation. Surprisingly, in the setting of established disease, IL-4 was not obligatory for the generation of the asthmatic phenotype (6, 7). In contrast, multiple lines of experimental evidence have demonstrated that IL-13 is a critical effector that is both necessary and, in some cases, sufficient for the allergic response. This includes studies that demonstrated that IL-13 blockade reverses airways hyperresponsiveness (AHR) and mucus metaplasia in antigen-sensitized and -challenged mice (8, 9), that an IL-13–pseudomonas toxin construct reverses many of the features of aspergillus-induced airways disease (10), and that IL-13–null mice fail to develop AHR after antigen sensitization and challenge, despite their ability to mount a vigorous Th2-biased inflammatory response (11). It also includes studies that demonstrate that the transgenic overexpression of IL-13 induces asthma-like eosinophilic inflammation, mucus metaplasia, airway fibrosis, and AHR in the murine lung (12). The central role of IL-13 in asthma and allergy is also highlighted by recent studies that demonstrated that the biologic effects of IL-9 and IL-25 are mediated via IL-13, and that histamine can induce IL-13 production in some experimental circumstances (13–16) (Figure 1).



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  		Figure 1. Schematic illustration of the IL-13 pathway in asthma and allergy. IL-13 is produced by a variety of cells, including CD4+ T cells, mast cells, and eosinophils. This process can be triggered by antigen in appropriately sensitized hosts and, under appropriate circumstances, by IL-9, IL-25, and histamine. IL-13 mediates its effects by binding to the IL-13 receptor which is a multimeric complex made up of IL-4R{alpha} and IL-13R{alpha}1. It also binds IL-13R{alpha}2, a decoy receptor, which downregulates IL-13 signaling. After receptor binding, the bulk of IL-13 effector pathway activation occurs via STAT-6 signaling. This regulates the expression of a variety of genes in target cells which generate tissue alterations. hCLCA1/mCLCA3, adenosine and EGFR may be involved in the mucus and epithelial alterations, VEGF in the blood vessel alterations, TGF-ß1 in airway fibrosis, MMPs, chemokines, and chemokine receptors in inflammation and IL-5 alterations in myocyte relaxation may contribute to AHR. As illustrated in the report by Vargafrig and Singer in this journal, leukotrienes play an important role in many of these responses. The LTs may be upstream of the signaling pathways as hypothesized in this figure. Alternatively, leukotrienes may be downstream of the target genes that are described.

 
In keeping with the animal studies described above, there is mounting evidence supporting the contention that IL-13 is a key mediator of human allergy and asthma. Numerous investigators have demonstrated exaggerated IL-13 gene expression and/or protein production in asthma and related disorders (2, 3). IL-13 levels also decrease with successful desensitization and steroid therapy (17), and robust blood T cell IL-13 production has been demonstrated to be a significant predictor of risk for atopy in a neonatal cohort evaluation (18). Studies of IL-13 have described a number of polymorphisms in the promoter and coding regions of this gene. They also highlighted the association of many of these polymorphisms with asthma or atopy (19–21). Studies of the polymorphism that replaces the arginine with a glycine at +110 have revealed an exciting mechanism that may underlie this association, because recombinant IL-13 with the Gln110 alteration binds IL-13R{alpha}2 (the decoy IL-13 receptor) with lower affinity than the wild-type molecule. This results in higher circulating levels of IL-13 in patients with this homozygous alteration (22).


   Mechanisms of IL-13 Effector Pathway Activation
Top
 Introduction
 Th2 Cells and IL-13...
 Mechanisms of IL-13 Effector...
Leukotrienes in Asthma
 The Intersection of IL-13...
 References
 
Because IL-13 is a critical mediator of asthma and allergy, recent attention has focused on the mechanisms that it uses to induce tissue alterations. As noted above, IL-13 is a potent stimulator of eosinophilic inflammation, airway fibrosis, mucus metaplasia, and AHR. These alterations are the result of IL-13 binding to the multimeric IL-13 receptor (which is made up of IL-13R{alpha}1 and IL-4R{alpha}) and the activation of STAT-6 signaling pathways. There is mounting evidence, however, that the effects of IL-13 are rarely a direct consequence of cytokine-receptor binding (23). Instead, IL-13 mediates its effects via its ability to regulate the expression of a wide range of downstream genes in inflammatory and structural target cells such as airway smooth muscle cells, macrophages, and epithelial cells (Figure 1). The contributions of these downstream genes have been defined in experiments in which the effector properties of IL-13 are characterized before and after treatment with neutralizing antibodies, experiments that compare the phenotypes that are induced by IL-13 in wild-type mice and mice with null mutants of these downstream genes, and studies in which transgenic IL-13 is expressed in mice that are wild type or null mutant at the specific target genes of interest. These studies have provided striking insights into the pathogenesis of IL-13–induced inflammation, mucus metaplasia, airway remodeling, and AHR. As illustrated in Figure 1, the inflammatory response is mediated by the ability of IL-13 to stimulate the production of a large number of chemokines (including eotaxin, eotaxin-2, MCP-1, MCP-2, MCP-3 and MCP-5, TARC, TECK, MDC, C10, MIP-1{alpha}, MIP-1ß, and MIP-3{alpha}) (24) which recruit inflammatory cells to the lung. Signaling via the CCR2 chemokine receptor and the induction of matrix metalloproteinase (MMP)-12 also plays crucial roles in this response (24, 25). The epithelial effects of IL-13 are mediated by the ability of IL-13 to increase epithelial cell proliferation via an epidermal growth factor receptor (EGFR)–TGF-{alpha}–dependent mechanism (26), and may involve adenosine, which induces mucus metaplasia in adenosine deaminase–null mutant mice (27). They may also involve the hCLCA1/mCLCA3 calcium-activated chloride channel, which is upregulated at sites of IL-13 elaboration and is necessary and sufficient for the development of goblet cell metaplasia and mucus hypersecretion in some experimental systems (28, 29). The fibrotic effects of IL-13 are mediated by its ability to stimulate and simultaneously activate transforming growth factor (TGF)-ß1 (30), whereas the vascular effects of IL-13 are likely the result of IL-13–stimulated vascular endothelial growth factor (31). Lastly, a variety of lines of evidence suggest that IL-13 induces AHR via a direct interaction with airway smooth muscle cells. The ability of IL-13 to reduce ß adrenoceptor–induced relaxation of cell stiffness in human airway smooth muscle cells via a mitogen-activated protein kinase–, IL-5–, and IL-4 R{alpha}–dependent pathway may contribute to this response (32).


   Leukotrienes in Asthma
Top
 Introduction
 Th2 Cells and IL-13...
 Mechanisms of IL-13 Effector...
 Leukotrienes in Asthma
The Intersection of IL-13...
 References
 
Over 60 years ago, slow reacting substance of anaphylaxis was appreciated as a spasmogenic activity in the effluent of anaphylaxed lung tissues (33–35). In 1979–80, Samuelson and coworkers discovered the chemical nature of LTs and demonstrated that slow reacting substance of anaphylaxis was the result of LTs in these experimental systems. Subsequent studies defined the 5-lipoxygenase (5-LO) metabolic pathway that converts membrane AA to leukotriene B4 and the cysteinyl leukotrienes (LTC4, -D4, and -E4) and the LT receptors CysLT1 and CysLT2. (33–35). They also demonstrated that these LT moieties are present in striking quantities in biologic samples from patients with asthma, and highlighted their ability to induce asthma-like phenotypes, including airway smooth muscle contraction, bronchospasm, tissue eosinophilia, and edema (33–35). Since 1987, clinical studies with compounds with anti-LT properties have been underway. These studies demonstrated that agents that block 5-LO and LT receptor antagonists can improve lung function, decrease symptomatology, and control aspects of pulmonary inflammation in asthma (33–35). Recent studies have also demonstrated that these agents may be able to control asthmatic airway fibrosis (36). By 1998, three chemically distinct cysteinyl LT receptor antagonists and one 5-LO inhibitor were available by prescription for the treatment of asthma. These were the first new therapies licensed for asthma in over 30 years. Their impact has been powerful, as reflected in the recent addition of LT regulators to the practice guidelines promulgated by a variety of medical organizations.


   The Intersection of IL-13 and LT
Top
 Introduction
 Th2 Cells and IL-13...
 Mechanisms of IL-13 Effector...
 Leukotrienes in Asthma
 The Intersection of IL-13...
References
 
LTs are produced by a variety of cells in the lung, including eosinophils, mast cells, and alveolar macrophages. Until recently, LT production was believed to be triggered by IgE-mediated activation of these tissues. The recent demonstration that IL-13 stimulates LT receptor transcription, expression, and function in monocytes and monocyte-derived macrophages (37) suggested that a more intimate relationship between Th2 inflammation, in particular IL-13, and LTs might exist. The nature of this relationship, however, has not been elucidated. In this issue of the AJRCMB, Vargafrig and Singer demonstrate an impressive and previously unappreciated relationship between IL-13 and lung LT (1). Specifically, they demonstrate that IL-13 increases the levels of mRNA encoding 5-LO and the levels of LTs in BAL fluids from mice. They also demonstrate that 5-LO inhibition and cysteinyl LT receptor antagonists decrease the ability of IL-13 to induce tissue eosinophilia and neutrophilia, AHR, mucus metaplasia, MUC5AC gene expression, vascular remodeling, and collagen deposition (1). This puts LT in the center of the IL-13 effector pathway. It also suggests that the benefits derived from LT antagonism may be, at least in part, the result of the ability of LT regulators to inhibit the effector properties of IL-13. These studies also raise some very interesting questions and issues. First, because the majority of the studies that were undertaken by Vargafrig and Singer employed acute protocols, their results cannot necessarily be extrapolated to chronic asthma. It will be important to know if LTs play a similarly important role in the pathogenesis of the chronic effector functions of IL-13 in the airway. In addition, the relationships between the LTs and the chemokine, TGF-ß1, EGFR/TGF-{alpha}, hCLCA1/mCLCA3, adenosine, MMP, and other IL-13 effector pathways need to be elucidated. The LTs may be upstream of these activation pathways, as speculated upon in Figure 1. Alternatively, LTs may only be upstream of selected IL-13 activation pathways or may be induced only after other pathways are activated. In the pharmaceutical industry, a significant amount of energy is presently being expended in efforts to identify agents that control the tissue effects of IL-13. It is only with a clear understanding of the relationships between the LTs and the other acute and chronic IL-13 effector pathways that we will be able to determine if blocking IL-13 directly has beneficial effects that are not seen with the LT regulators. In the meantime, it is reasonable to place LT antagonists on the list of interventions that can be used to control diseases characterized by IL-13 excess such as asthma. Because IL-13 overproduction is also seen in idiopathic pulmonary fibrosis, scleroderma, nodular sclerosing Hodgkin's disease, chronic obstructive pulmonary disease, and schistosomiasis, the work of Vargaftig and Singer suggest that LT regulators may also be therapeutically useful in the treatment of these disorders (38–41).

Received in original form January 28, 2003


   References
Top
 Introduction
 Th2 Cells and IL-13...
 Mechanisms of IL-13 Effector...
 Leukotrienes in Asthma
 The Intersection of IL-13...
 References
 

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