IL-13 is a critical cytokine at sites of Th2 inflammation. In these locations it mediates its effects via a receptor complex, which contains IL-4Rα and IL-13Rα1. A third, high-affinity IL-13 receptor, IL-13Rα2, also exists. Although it was initially felt to be a decoy receptor, this has not been formally demonstrated and the role(s) of this receptor has recently become controversial. To define the role(s) of IL-13Rα2 in IL-13-induced pulmonary inflammation and remodeling, we compared the effects of lung-targeted transgenic IL-13 in mice with wild-type and null IL-13Rα2 loci. We also investigated the effect of IL-13Rα2 deficiency on the OVA-induced inflammatory response. In this study, we show that in the absence of IL-13Rα2, IL-13-induced pulmonary inflammation, mucus metaplasia, subepithelial fibrosis, and airway remodeling are significantly augmented. These changes were accompanied by increased expression and production of chemokines, proteases, mucin genes, and TGF-β1. Similarly, an enhanced inflammatory response was observed in an OVA-induced phenotype. In contrast, disruption of IL-13Rα2 had no effect on the tissue effects of lung-targeted transgenic IL-4. Thus, IL-13Rα2 is a selective and powerful inhibitor of IL-13-induced inflammatory, remodeling, and physiologic responses in the murine lung.
The cytokines IL-4 and IL-13 are important mediators of Th2 inflammation in human asthma and in models of asthma and parasitic infection (1, 2, 3). These cytokines have overlapping and distinct biologic properties. The common effector responses include the ability to stimulate VCAM expression and IgE production (4, 5). Their unique properties are nicely illustrated in the asthma and parasite models where IL-13 plays a more important role than IL-4 in the development of airway hyperresponsiveness (AHR),3 mucus metaplasia, and pulmonary fibrosis (1, 6, 7) and the expulsion of Nippostrongyloides (8) while IL-4 plays a central role in Th2 cell development (9, 10). IL-13 mediates its effects via a dimeric receptor made up of IL-4Rα and IL-13Rα1 (type II). IL-13 initially binds IL-13Rα1 with low affinity and then IL-4Rα binds to generate the high-affinity cytokine-binding heterodimer (11). IL-4 also binds to this receptor complex. This may explain the overlapping effector responses of IL-4 and IL-13 (12, 13). However, IL-4 can also bind the type I IL-4 receptor, which is made up of IL-4Rα and the γ common chain, a shared receptor subunit for IL-2, IL-7, IL-9, and IL-15 (14).
IL-13Rα2, the third component of the IL-13 receptor system, binds IL-13 exclusively and with high affinity. This receptor lacks a signaling motif and exists in membrane-bound and soluble forms. These findings led to the initial belief that IL-13Rα2 is a decoy receptor for IL-13 (15, 16). Indeed, overexpression of IL-13Rα2 diminished IL-13 signaling (17, 18) and treatment with an IL-13Rα2-Fc fusion protein prevented IL-13-induced liver fibrosis in a mouse model of schistosomiasis (19, 20). It was also reported that lysophosphatidic acid was able to inhibit IL-13 signaling in vitro via up-regulation of IL-13Rα2 (21). However, a recent report has questioned this concept. Using a small interfering RNA approach these investigators implicated IL-13Rα2 in the ability of bleomycin to activate the transcription factor AP-1 and induce the production of TGF-β and the generation of tissue fibrosis (22). The expression of IL-13Rα2 is regulated by both Th1 and Th2 cytokines in vitro and in vivo (23). In addition, IL-13Rα2 has been shown to have inhibitory effects on IL-4-dependent signal transduction in glioblastoma cells ex vivo (24). However, the biological roles of IL-13Rα2 in Th2 cytokine-mediated pulmonary diseases such as asthma are not well understood. Specifically, the ability of IL-13Rα2 to regulate IL-13- and IL-4-induced tissue responses and the role(s) of IL-13Rα2 in Th2 cytokine-induced tissue fibrosis have not been adequately defined.
To further understand the biology of IL-13Rα2 in Th2 cytokine-induced pathologies, we characterized the effects of transgenic (Tg) IL-13 and IL-4 in mice with wild-type (WT) and null (−/−) IL-13Rα2 loci. These studies demonstrate that, in the absence of IL-13Rα2, IL-13-induced inflammation and mucus metaplasia are markedly enhanced. Similarly, IL-13-induced pulmonary fibrosis and TGF-β1 production were also enhanced in IL-13Rα2−/− animals. In contrast, IL-4-induced pulmonary responses were not altered in IL-13Rα2−/− animals. Thus, IL-13Rα2 is an IL-13-specific receptor that antagonizes inflammatory, remodeling, and physiologic responses in the murine lung.
Materials and Methods
All studies on animals were approved by the Institutional Animal Care and Use Committee of Yale University and were in accordance with the guidelines of humane treatment and use of animals by National Institutes of Health. Lung-specific inducible IL-13 Tg (CC10-rtTA-IL-13) mice on C57BL/6 genetic background were generated and described previously by our laboratories (25). These mice carry two transgenes; the reverse tetracycline transactivator (rtTA) directed by CC10 promoter to the lung and tetracycline response element and minimum CMV promoter-controlled IL-13. The IL-13 transgene was activated by adding doxycycline (Dox) to the animal’s drinking water. Dox was administered at 500 mg/L with 4% sucrose and kept in dark brown bottles to prevent light-induced degradation. In these experiments, 1-mo-old mice were randomized to receive normal water or Dox water for 4 wk. IL-4 Tg mice on C57BL/6 background (CC10-IL-4) in which IL-4 is constitutively targeted to the lung were generated and described previously (7). IL-13Rα2 null mutant mice on C57BL/6 background were generated and provided by Dr. M. Grusby of Harvard University School of Public Health (20). The CC10-rtTA-IL-13+ mice were labeled as IL-13+ mice and the CC10-IL-4+ mice as IL-4+ mice.
Generation of IL-13- and IL-4 Tg mice with IL-13Rα2 null mutation
We crossbred mice to obtain IL-13+ mice with a homozygous null mutation (−/−) of IL-13Rα2. First, CC10-rtTA-IL-13 transgene-positive mice with normal IL-13Rα2 loci (IL-13+/IL-13Rα2+/+) were bred with IL-13(WT) mice with a null mutation of IL-13Rα2 (IL-13(WT)/IL-13Rα2−/−). The transgene-positive progeny, IL-13+/IL-13Rα2+/−, of this cross was then bred with IL-13(WT)/IL-13Rα2+/− mice. This provided the IL-13(WT)/IL-13Rα2+/+, IL-13(WT)/IL-13Rα2−/−, IL-13+/IL-13Rα2+/+, and IL-13+/IL-13Rα2−/− mice that were used in these studies. These mice were kept on normal drinking water until they were at least 1 mo of age. They were then randomized to receive regular water or Dox water for 4 wk. CC10-IL-4 mice were crossed with IL-13Rα2−/− mice in the same fashion as above to obtain IL-4+/IL-13Rα2+/+ and IL-4+/IL-13Rα2−/− mice. These mice were used for the experiments when they were 6–8 wk old.
OVA-induced mouse asthma model
To understand the role of IL-13Rα2 in allergen-induced pulmonary inflammation, we conducted experiments to compare WT mice with IL-13Rα2−/− mice in response to OVA allergen stimulation. WT C57BL/6 mice were purchased from The Jackson Laboratory. Allergen sensitization and challenges were conducted as previously described (26). Briefly, 6-wk-old mice were divided into four groups: WT mice treated with PBS, WT with OVA, IL-13Rα2−/− with PBS, and IL-13Rα2−/− with OVA. Sensitization was started by injection i.p. of 100 μg of OVA (grade V; Sigma-Aldrich) mixed with 2 mg of aluminum hydroxide (alum) in 200 μl of PBS on day 1 and followed by a boost on day 7. The mice were challenged intranasally with 1% OVA daily for three times starting on day 14 and sacrificed on day 18 and the BAL and lung tissues were obtained and stored until evaluation.
Bronchoalveolar lavage, lung volume, and histology assessments
After anesthetization, the trachea of the mouse was isolated and cannulated. BAL fluid was obtained for the assessment of lung inflammation. The lung volume was determined using pressure fixation and volume displacement as previously described (27). Then a median sternotomy was performed, and the pulmonary vascular bed was perfused with PBS through the right heart ventricle. The lung was inflated with Streck tissue fixative to a fixed pressure of 25 cm of H2O, embedded in paraffin, sectioned at 5 μm, and stained. H&E, Masson’s trichrome, and periodic acid-Schiff with diastase stains were performed in the Research Histology Laboratory of the Department of Pathology at Yale University School of Medicine. Alveolar size was estimated from the mean chord length of the airspace as previously described by our laboratory (25, 27).
Quantification of cytokines and chemokines
IL-13, IL-4, chemokines, and total and active TGF-β1 in the BAL were measured using ELISA kits (R&D Systems) according to the manufacturer’s instructions.
Quantification of lung collagen
The collagen content was determined by quantifying total soluble collagen using the Sircol Collagen Assay Kit (Biocolor) according to the manufacturer’s instructions. The data are expressed as the collagen content of the entire right lung.
Western slot blot analysis
An equal volume (10 μl) of BAL fluid from each kind of mice was loaded onto an Immobilon polyvinylidene difluoride membrane (Millipore) in a slot-blot apparatus. Mouse monoclonal anti-MUC2 and monoclonal anti-MUC5AC were used as primary Abs (Neomarker). A goat anti-mouse IgG conjugated to HRP was used as secondary Ab (Santa Cruz Biotechnology). Protein detection was accomplished with a Super Signal West Femto Maximum Kit (Pierce).
Normally distributed data were analyzed by Student’s t test or ANOVA as appropriate and were expressed as mean ± SEM. Data that were not normally distributed were assessed for significance using the Wilcoxon rank sum test. Differences with a p value of 0.05 or less were considered significant.
Role(s) of IL-13Rα2 in IL-13-induced pulmonary inflammation
To begin to understand the biologic roles of IL-13Rα2, we compared the inflammatory responses in IL-13 Tg mice with WT and null IL-13Rα2 loci. The number and differential of BAL cells from Tg− mice on normal and Dox water were similar regardless of their IL-13Rα2 genotype (Fig. 1, A and B). In accord with previous studies from our laboratory (1), IL-13 production increased BAL total cells and the recovery of macrophages, eosinophils, and lymphocytes (Fig. 1,B). IL-13 caused similar increases in lung tissue (data not shown). These effects were further enhanced in the absence of IL-13Rα2 because BAL cellularity, BAL macrophage, lymphocyte, and eosinophil recovery and tissue inflammation were increased in Tg mice with null IL-13Rα2 loci (Fig. 1, A and B, and data not shown).
To understand the mechanisms that might contribute to the enhanced IL-13-induced pulmonary inflammation in IL-13Rα2 null mice, we compared the expression of selected chemokines in lungs and BAL fluids from IL-13 Tg mice with WT and null IL-13Rα2 loci. In Tg− mice with WT or null IL-13Rα2 loci, the levels of mRNA encoding eotaxin/CCL-11 and MCP-1/CCL2 were comparable at baseline (Fig. 1,C). As previously reported (30, 31), IL-13 significantly increased the levels of mRNA encoding these chemokines in IL-13 Tg mice with WT IL-13Rα2 loci (Fig. 1,C). Importantly, in the absence of IL-13Rα2, the ability of IL-13 to stimulate the expression of the above chemokines was further increased (Fig. 1,C). These mRNA alterations were paralleled with changes in the protein levels of these chemokines in the BAL (Fig. 1 D). Several other chemokines, eotaxin-2/CCL21, MCP-2/CCL8, MCP-3/CCL7, MIP-1α/CCL-3, MIP-1β/CCL4, and MIP-2/CXCL-2/3, showed similar changes in mRNA by RT-PCR (data not shown). Thus, IL-13Rα2 inhibits IL-13-induced pulmonary inflammation, in part, by limiting IL-13-stimulated chemokine production.
Roles of IL-13Rα2 in IL-13-induced mucus metaplasia
Studies were next undertaken to define the roles of IL-13Rα2 in IL-13-induced mucus metaplasia. periodic acid-Schiff with diastase-stained cells were not appreciated in the airways from Tg− mice with WT or null IL-13Rα2 loci. As expected, IL-13 was a potent stimulator of mucus metaplasia (Fig. 2,A). IL-13 also enhanced MUC5AC mucin gene expression and stimulated mucus release into BAL fluids (Fig. 2, B and C). Each of these responses was limited by IL-13Rα2 with goblet cell hyperplasia, mucin gene expression, and mucus secretion all being significantly increased in comparisons of Tg+ mice with null vs WT IL-13Rα2 loci (Fig. 2, A–C).
Roles of IL-13Rα2 in IL-13-induced pulmonary fibrosis and increased TGF-β1
Previous studies from our laboratory demonstrated that IL-13 induces pulmonary fibrosis, in part, via its ability to induce and activate TGF-β1 and that this activation is partially mediated by matrix metalloproteinase (MMP) 9 (1, 32). Studies were thus undertaken to define the roles of IL-13Rα2 in IL-13-induced collagen deposition and TGF-β1 production and activation. As previously reported, IL-13 caused peribronchial fibrosis and induced and activated TGF-β1 (Fig. 3, A, B, D, and E). These responses were further enhanced in mice with null mutations of IL-13Rα2 which manifested significantly increased collagen deposition, TGF-β1 production and gene expression, MMP-9 expression, and TGF-β1 activation when compared with IL-13 Tg mice with WT IL-13Rα2 loci (Fig. 3, A–E). These studies demonstrate that IL-13Rα2 inhibits IL-13-induced fibrosis, the production of TGF-β1, and the TGF-β1 activator MMP-9 and TGF-β1 activation in the murine lung.
Role of IL-13Rα2 in IL-13-induced alveolar remodeling
We demonstrated previously that Tg IL-13 causes alveolar remodeling characterized by alveolar simplification and enlargement (25). To define the role of IL-13Rα2 in these alterations, we compared the alveoli in IL-13 Tg mice with WT and null IL-13Rα2 loci. Lung size, lung volume, and alveolar size were similar in Tg− mice with WT and null IL-13Rα2 loci on normal and Dox water (Fig. 4, A–C, and data not shown). In contrast, Tg IL-13 caused an impressive increase in these parameters in mice that had intact IL-13Rα2 loci (Fig. 4, A–C). In all cases, these effects were inhibited by IL-13Rα2. This was readily appreciated in lung volume, morphometric, and histologic comparisons of Tg+ mice with WT and null IL-13Rα2 loci (Fig. 4, A–C, and data not shown).
We reasoned that a deficiency of IL-13Rα2 could modulate IL-13-induced alveolar remodeling by increasing the production of proteases in the lung. To test this, we compared the levels of mRNA encoding MMPs and cathepsins in the lung of Tg mice with WT or null IL-13Rα2 loci. Comparable levels of mRNA encoding MMP-2, MMP-9, and cathepsin S were noted in lungs from Tg− mice on normal or Dox water regardless of their IL-13Rα2 genotype (Figs. 3,C and 4, D and E). In accord with previous studies from our laboratory and others, the levels of mRNA encoding each of these proteases was increased in IL-13 Tg+ mice with WT IL-13Rα2 loci (25). Interestingly, in the absence of IL-13Rα2, the ability of IL-13 to stimulate the accumulation of mRNA encoding MMP-2, MMP-9, and cathepsin S was further enhanced (Figs. 3,C and 4, D and E). When viewed in combination, these studies demonstrate that IL-13Rα2 interacts with IL-13 to inhibit alveolar remodeling and that these effects may be mediated by alterations in MMP-2, MMP-9, and cathepsin S.
Role of IL-13Rα2 in OVA allergen-induced inflammation
IL-13 plays a central role in animal models of allergen-induced pulmonary inflammation and airway hyperresponsiveness (AHR) (33, 34). Thus, it is possible that IL-13Rα2 has some effect on the host response to allergen stimulation through its interaction with IL-13, which is induced in the process. We examined the pulmonary inflammation of IL-13Rα2−/− mice after OVA allergen sensitization and challenge in comparison to that of WT mice. As shown in Fig. 5, A and B, WT and IL-13Rα2−/− mice without allergen stimulation (PBS groups) had baseline cell counts in the BAL and no infiltration of inflammatory cells in the lung tissue. As expected, WT mice sensitized and challenged with OVA showed significantly increased infiltration of inflammatory cells in the BAL and in the lung tissue (Fig. 5, A and B). More important, disruption of IL-13Rα2 gene further enhanced the inflammatory response, as evidenced by significantly increased cell infiltration, particularly eosinophils and lymphocytes, in the BAL and in the lung tissue (Fig. 5, A and B). These changes are because of the increased tissue response in the absence of IL-13Rα2, not because of the alterations in IL-13 production, because OVA-sensitized and -challenged WT and IL-13Rα2 knockout mice had comparable levels of IL-13 in the BAL (68.4 ± 24.9 vs 58.8 ± 9.1 pg/ml, respectively). Similarly, the levels of IL-4 and IL-5 in the BAL were not significantly different between the two groups of mice (data not shown).
Role of IL-13Rα2 in IL-13 elaboration
A deficiency of IL-13Rα2 could modify IL-13-induced tissue responses by altering the production of Tg IL-13 or modulating IL-13 effector responses. To determine whether alterations in IL-13Rα2 regulated the production of IL-13, we compared the levels of this cytokine in BAL from Tg+ and Tg− mice with WT and null IL-13Rα2 loci. IL-13 was not detected in BAL fluids of Tg− mice. In contrast, significant levels of BAL IL-13 were detected in Tg+ mice, with the levels of IL-13 ranging from 0.5 to 1.5 ng/ml (0.75 ng/ml; SEM 0.012). Similar levels of IL-13 were seen in the BAL fluid of Tg+ mice with null IL-13Rα2 loci (data not shown). Thus, a null mutation of IL-13Rα2 altered IL-13-induced tissue responses by modifying IL-13 effector pathway activation without affecting the Tg IL-13 production.
IL-13Rα2 deficiency and IL-4-induced lung pathology
Studies were undertaken to determine whether IL-13Rα2 had similar effects on IL-4-induced responses in the murine lung. This was done by generating lung-specific IL-4 Tg mice with WT and null IL-13Rα2 loci and comparing the phenotypes induced by IL-4 in these animals. As described previously, IL-4 Tg mice produced the cytokine in BAL in the range of 0.148–5.9 ng/ml (3.5 ± 0.025), comparable with that of IL-13 in the BAL of CC10-rtTA-IL-13 mice. In accord with previous reports from our laboratory and others (7, 35, 36), Tg IL-4 caused an eosinophil and mononuclear cell-rich inflammatory response, (Fig. 6,A), mucus metaplasia with enhanced mucin gene expression and mucus secretion (Fig. 6, B and C), pulmonary fibrosis with enhanced TGF-β1 expression (Fig. 6,D), and alveolar remodeling (Fig. 6 E). However, in contrast to the results seen with Tg IL-13, no further exacerbation was seen in the IL-4 Tg mice in the absence of IL-13Rα2. When viewed in combination, these studies demonstrate that IL-4-induced tissue responses are not altered by the ablation of IL-13Rα2.
Exaggerated levels of IL-13 production have been implicated in the pathogenesis of a variety of disorders, including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, scleroderma, hepatic fibrosis, and nodular sclerosing Hodgkin’s disease (37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47). The remarkable effects that IL-13 can have in these disorders can be appreciated in studies that highlighted the ability of IL-13 to induce tissue inflammation, cathepsin- and MMP-mediated proteolysis, and TGF-β1-induced tissue fibrosis (25, 32, 48). Thus, studies have been undertaken to define the pathways that control IL-13 effector function. These studies demonstrated that IL-13 can be controlled at a number of levels including intracellular inhibitors of IL-13 signaling such as SHIP-1, Src homology region 2 domain-containing phosphatase 1, and suppressor of cytokine signaling (24, 49, 50). Another level of regulation has been proposed to occur at the level of IL-13Rα2, which has been described as a decoy receptor for IL-13 (19, 51). However, this has been questioned in a bleomycin lung injury model in which IL-13Rα2 was shown to play a critical role in the induction of TGF-β1 and the generation of pulmonary fibrosis (22). To define the roles of IL-13Rα2 in IL-13-induced pulmonary pathology, we used Tg mice in which IL-13 was selectively targeted to the lung and bred them with IL-13Rα2 null mice. We then compared the effects of IL-13 in mice that were sufficient and deficient in IL-13Rα2. Our findings demonstrated that, in the absence of IL-13Rα2, IL-13-induced inflammation, mucus metaplasia, fibrosis, and alveolar remodeling are significantly enhanced. Furthermore, this is supported by the observation that IL-13Rα2 deficiency significantly enhanced OVA allergen-induced pulmonary inflammation, in which IL-13 is known to play a critical role. These data indicate that IL-13Rα2 is a negative regulator of IL-13 effector function in the lung.
It is now believed that asthma is a chronic inflammatory disease of the airway, in which exaggerated production of Th2 cytokines such as IL-13 plays a major role. Furthermore, airway remodeling and AHR are believed to be consequences of this tissue inflammatory response. Our studies add to our understanding of this inflammatory response by demonstrating that IL-13-induced inflammation, mucus metaplasia, airway fibrosis, alveolar remodeling, and IL-13 stimulation of chemokines, mucin genes, proteases, and TGF-β1 are increased in animals with null mutations of IL-13Rα2. Since IL-13Rα2 is stimulated by Th2 cytokines (23), these findings suggest that IL-13Rα2 serves as a feedback mechanism that is designed to control local Th2 inflammatory responses. This may be particularly important for the alveolar remodeling and compliance changes that are seen in the IL-13 Tg mice because similar emphysema-like compliance alterations have been documented in asthmatics where they correlate with disease severity (52, 53).
Tissue fibrosis is part of the airway remodeling response in asthma and a major cause of morbidity and mortality in several other pulmonary and extrapulmonary disorders (54, 55). Studies in a variety of systems have demonstrated that IL-13 is a major mediator of these fibrotic responses (42, 51, 56). A number of studies demonstrated that IL-13 causes tissue fibrosis, at least in part, by inducing and activating TGF-β1 (22, 32), which is dependent on MCP-1/CCL2 and MMP-9, respectively (30, 32). The present studies add to our understanding of this important fibrogenic pathway by demonstrating that IL-13Rα2 plays a critical role in its regulation. Specifically, in the absence of IL-13Rα2, the fibrogenic effects of IL-13 are significantly increased, along with augmented induction of MMP-9, stimulation of MCP-1/CCL2, and induction and activation of TGF-β1. Importantly, IL-13Rα2 has recently been shown to be involved in induction of TGF-β1 in a bleomycin-induced lung fibrosis mouse model (22). In this study, Fichtner-Feigl et al. (22) administered IL-13Rα2-specific small interfering RNA encapsulated in a HVJ envelope to the lung and reported that it blocked the production of TGF-β1 and collagen deposition, suggesting that IL-13Rα2 functions as a signaling receptor that mediates the TGF-β1 stimulatory and profibrotic effects of IL-13 (22). These findings appear to conflict with our findings and those by others in murine schistosomiasis models (38, 42, 57) that IL-13Rα2 inhibits TGF-β1 production and tissue fibrosis. However, upon deeper analysis, one can envision a number of possible explanations. One relates to technical differences in the studies because the HVJ envelope protein used in their study has been shown to stimulate the production of the potent antifibrotic Th1 cytokine IFN-γ (58, 59). In addition, the divergent results may reflect true differences in the effects of the different fibrogenic stimuli that were used or the differential utilization of IL-13Rα2 in the airway vs the parenchyma of the lung. Additional investigation will be required to evaluate these possibilities.
IL-13 was originally discovered as an IL-4-like molecule and presumed to have an identical effector profile. It has since become clear that IL-13 and IL-4 differ in their effector properties with IL-4 and IL-13 playing more prominent roles in the initiation and the effector phases of Th2 inflammation, respectively (1, 33, 34, 60). Studies of the IL-13 and IL-4 receptors have provided insights into the mechanisms that might contribute to the similarities and differences in the effector profiles of these cytokines. As noted above, IL-13 signals via the type II heterodimeric receptor complex involving IL-4Rα and IL-13Rα1 (61). IL-4 can also bind this receptor complex. In addition, IL-4 can bind to the type I IL-4R, which contains IL-4Rα and the γ common chain (14, 61). Because our studies demonstrated that IL-13Rα2 inhibited IL-13 effector pathway activation and IL-4 can interact with the type II receptor complex, we undertook studies to determine whether IL-13Rα2 also altered IL-4 effector responses. These studies demonstrated that null mutation of IL-13Rα2 did not alter IL-4-induced tissue inflammation, mucus metaplasia, peribronchial fibrosis, or lung volume alteration. These findings are in accord with the contention that IL-13Rα2 is specific for IL-13 (61). However, it is also possible that some of these IL-4-induced responses are mediated via the type I IL-4R complex and thus would not be expected to interact with IL-13Rα2.
In summary, our studies demonstrate that IL-13Rα2 is a critical and cytokine-specific negative regulator of the IL-13 effector pathway in the lung in the IL-13 Tg system and in the OVA allergen-induced asthma model and that the interactions between IL-13 and IL-13Rα2 decrease IL-13-induced chemokine (eotaxin/CCL11 and MCP-1/CCL2) and protease (MMP-2, MMP-9, and cathepsin S) expression, mucin expression, and secretion, and TGF-β1 induction and activation. All in all, these observations are compatible with the concept that IL-13Rα2 acts as a decoy receptor for IL-13 in the murine lung. They also suggest that the manifestations of asthma and or other IL-13-mediated diseases may benefit from treatment with agents that function like or augment the expression of IL-13Rα2 to neutralize IL-13 and to inhibit IL-13-induced tissue responses.
The authors have no financial conflict of interest.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
This work was supported by National Institutes of Health Grants AI55064 (to T.Z.); HL074095 and HL079349 (to Z.Z.); and HL64242, HL078744, HL56389, and HL081639 (to J.A.E.).
Abbreviations used in this paper: AHR, airway hyperresponsiveness; WT, wild type; rtTA, reverse tetracycline transactivator; Dox, doxycycline; BAL, bronchoalveolar lavage; Tg, transgenic; MMP, matrix metalloproteinase.