IL-13 is a major stimulator of inflammation and tissue remodeling at sites of Th2 inflammation. In Th2-dominant inflammatory disorders such as asthma, IL-11 is simultaneously induced. However, the relationship(s) between IL-11 and IL-13 in these responses has not been defined, and the role(s) of IL-11 in the genesis of the tissue effects of IL-13 has not been evaluated. We hypothesized that IL-11, signaling via the IL-11Rα-gp130 receptor complex, plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of IL-11, IL-11Rα, and gp130 in lungs from wild-type mice and transgenic mice in which IL-13 was overexpressed in a lung-specific fashion. We simultaneously characterized the effects of a null mutation of IL-11Rα on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11Rα. They also demonstrate that IL-13 is a potent stimulator of inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death in mice with wild-type IL-11Rα loci and that these alterations are ameliorated in the absence of IL-11Rα. Lastly, they provide insight into the mechanisms of these processes by demonstrating that IL-13 stimulates CC chemokines, matrix metalloproteinases, mucin genes, and gob-5 and stimulates and activates TGF-β1 via IL-11Rα-dependent pathways. When viewed in combination, these studies demonstrate that IL-11Rα plays a key role in the pathogenesis of IL-13-induced inflammation and remodeling.

Interleukin-13 is a pleiotropic 12-kDa product of a gene on chromosome 5 at q31 that is produced in large quantities by stimulated Th2 cells. It was originally described as an IL-4-like molecule based on shared effector properties, including the ability to stimulate IgE production. Subsequent studies demonstrated that IL-13 and IL-4 often play distinct roles in biology. A prominent aspect of this distinction is the appreciation that IL-4 plays a key role in Th2 cell differentiation and response generation, whereas IL-13 contributes as the major effector of Th2 inflammation and tissue remodeling (1, 2, 3, 4). In accord with these observations, IL-13 dysregulation has been documented, and IL-13 has been implicated in the pathogenesis of a variety of diseases characterized by inflammation and tissue remodeling, including asthma, idiopathic pulmonary fibrosis, scleroderma, viral pneumonia, hepatic fibrosis, nodular sclerosing Hodgkin’s disease, and chronic obstructive pulmonary disease (COPD)4 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). Studies from our laboratory and others have demonstrated that IL-13 mediates its tissue effects by activating a broad array of downstream target genes, including chemokines, matrix metalloproteinases (MMPs), TGF-β1, and chitinases (12, 13, 14, 15, 16). The importance of IL-6-type cytokines in the generation of the effects of IL-13, however, have not been investigated.

IL-11 is a multifunctional IL-6-type cytokine with diverse biologic properties, including the ability to stimulate hemopoiesis, thrombopoiesis, megakaryocytopoiesis, and bone resorption; regulate macrophage differentiation; and confer mucosal protection after chemotherapy and radiation therapy (17, 18, 19, 20, 21, 22). These effects are mediated by a multimeric receptor that contains a ligand-binding α subunit, IL-11Rα, and the ubiquitous β subunit, gp130, that triggers intracellular signaling (18, 23, 24). Previous studies from our laboratory and others demonstrated that, like IL-13, IL-11 is expressed in an exaggerated fashion in the dysregulated Th2 response in the asthmatic airway (25). Although IL-11 can inhibit Th1 responses, inhibit the production of Th1-related cytokines such as IL-12, and shift inflammation in a Th2 direction (22, 26, 27, 28, 29), little else is known about the role(s) of IL-11 in the generation and/or expression of Th2 tissue responses. In particular, interactions between IL-11 and IL-13 have not been defined, and a role for IL-11 in the genesis of IL-13-induced pathologies has not been established.

We hypothesized that IL-11 signaling plays a key role in IL-13-induced Th2 inflammation. To test this hypothesis, we characterized the expression of IL-11, IL-11Rα, and gp130 in lungs from wild-type (WT) mice and mice in which IL-13 was overexpressed in a lung-specific fashion. We also characterized the effects of a null mutation of IL-11Rα on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 is a potent stimulator of IL-11 and IL-11Rα. They also demonstrate that IL-11Rα plays a key role in IL-13-induced inflammation, fibrosis, hyaluronic acid (HA) accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure and death. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates CC chemokines, MMPs, mucin genes, and gob-5 and stimulates and activates TGF-β1 via IL-11Rα-dependent pathways.

CC10-IL-13 transgenic mice were generated in our laboratory, bred onto a C57BL/6 background, and used in these studies. These mice use the Clara cell 10-kDa protein (CC10) promoter to target IL-13 to the lung. The methods used to generate and characterize these mice were described previously (30). In this modeling system, IL-13 caused a mononuclear cell- and eosinophil-rich tissue inflammatory response, alveolar enlargement, subepithelial and parenchymal fibrosis, mucus metaplasia, and respiratory failure and death, as previously described (12, 13, 30).

IL-11Rα-null mice (IL-11Rα−/−) were provided by Drs. L. Robb and C. Glenn Begley (Walter and Eliza Hall Institute, Victoria, Australia) (31, 32). These mice were bred for more than eight generations onto a C57BL/6 genetic background. CC10-IL-13 mice with WT+/+ and null−/− IL-11Rα loci were generated by breeding the IL-13 transgenic (Tg+) mice with the IL-11Rα−/− animals. Genotyping was accomplished as previously described (30, 32). Littermate control WT mice with (+/+) or without (−/−) IL-11Rα loci were used as controls.

Lung inflammation was assessed by BAL as previously described (13, 33). The BAL samples from each animal were then pooled and centrifuged. The number and types of cells in the cell pellet were determined as previously described (12, 13). The supernatants were stored at −20°C until used.

Animals were anesthetized, the trachea was cannulated, and the lungs were removed and inflated with PBS at 25 cm. The size of each lung was evaluated via volume displacement, and alveolar size was estimated from the mean chord length of the airspace, as previously described by our laboratory (13). Chord length increases with alveolar enlargement.

Animals were killed, a median sternotomy was performed, and right heart perfusion was accomplished with calcium- and magnesium-free PBS. The heart and lungs were then removed en bloc, inflated at 25 cm pressure with neutral-buffered 10% formalin, fixed in 10% formalin, embedded in paraffin, sectioned, and stained. H&E, Mallory’s Trichrome, and periodic acid-Schiff with diastase stains were performed at Yale University School of Medicine.

The levels of mRNA encoding IL-11 and IL-11Rα were evaluated with a commercial RNase protection assay (BD RiboQuant; BD Biosciences) as described by the manufacturer. Other mRNA levels were evaluated by RT-PCR analysis as previously described (13). The primers used have been described previously (12, 13, 15, 16). For each cytokine, the optimal numbers of cycles that will produce a quantity of cytokine product that is directly proportional to the quantity of input mRNA was determined experimentally. β-Actin was used as an internal standard. Amplified PCR products were detected using ethidium bromide gel electrophoresis, quantitated electronically, and confirmed by nucleotide sequencing.

BAL IL-13 and chemokine levels were quantitated using commercial ELISA kits (R&D Systems) according to the manufacturer’s instructions.

α-Smooth muscle actin and myosin H chain staining cells were evaluated by immunohistochemistry as previously described by our laboratory (15). The primary Abs were obtained from DakoCytomation. Specificity was assessed by comparing the staining of serial sections that were incubated in the presence and the absence of the primary Ab.

Collagen content was determined biochemically by quantifying total soluble collagen using the Sircol collagen assay kit (Biocolor) according to the manufacturer’s instructions (15). The data are expressed as the collagen content of the entire right lung. Collagen was also assessed morphometrically using picosirius red staining, performed as described previously by our laboratory (15). These data are expressed as the percentage of the histologic section with picosirius red staining.

The levels of BAL HA were measured using a competitive ELISA using biotinylated HA-binding protein as described previously (34, 35). Microtiter plates were coated with HA by combining rooster comb HA, carbodiimide HCl, and HCl. Samples were incubated with biotinylated HA-binding protein for 1 h and then added to the wells. The plate was then agitated, washed, developed with HRP-streptavidin, and exposed to peroxidase substrate for 30 min. OD at 405 nm was evaluated. Samples were compared with a simultaneously performed standard curve.

The levels of total and bioactive TGF-β1 were evaluated by ELISA (R&D Systems) using untreated and acid-treated BAL fluids according to the manufacturer’s instructions.

Adult 6- to 8-wk-old Tg and Tg+ mice with WT or null mutant IL-11Rα loci were exposed to room air (controls) or continuously to 100% O2 in a Plexiglas chamber as previously described (19, 36). All protocols were reviewed and approved by the institutional animal care and use committee at Yale University School of Medicine.

Normally distributed data are expressed as the mean ± SEM and assessed for significance by Student’s t test or ANOVA as appropriate. Data that were not normally distributed were assessed for significance using the Wilcoxon rank-sum test.

Studies were undertaken to define the effects of IL-13 on IL-11 and its receptor components in murine lung. These studies demonstrated that transgenic IL-13 is a potent stimulator of the expression of IL-11 and IL-11Rα. These effects were readily apparent at all time points evaluated (1–4 mo; Fig. 1 and data not shown). The induction of IL-11 was associated with similar increases in the levels of mRNA encoding other IL-6-type cytokines, including IL-6 and LIF (Fig. 1). A modest increase in gp130 expression was also observed (Fig. 1). Similar alterations in M-CSF, GM-CSF, stem cell factor, L32, and GAPDH, however, were not found. The alterations in IL-11Rα were also at least partially specific, because comparable alterations in the expression of IL-6Rα and IFN-γRα were not observed (Fig. 1). These studies demonstrate that IL-13 is a potent stimulator of IL-11 and the α subunit of its receptor in murine lung.

FIGURE 1.

IL-13 regulation of IL-11Rα and IL-11. Lungs were obtained from 2-mo-old CC10-IL-13 Tg and Tg+ mice, and the levels of mRNA encoding the noted cytokines, proteins, and receptors were evaluated using RNase protection. Each lane represents an individual animal.

FIGURE 1.

IL-13 regulation of IL-11Rα and IL-11. Lungs were obtained from 2-mo-old CC10-IL-13 Tg and Tg+ mice, and the levels of mRNA encoding the noted cytokines, proteins, and receptors were evaluated using RNase protection. Each lane represents an individual animal.

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To address the importance of IL-11 in the pathogenesis of IL-13-induced tissue inflammation, CC10-IL-13 transgenic mice were bred with IL-11Rα−/− mice. The inflammatory responses in IL-13 Tg+ mice with WT and null IL-11Rα loci were then compared. As previously reported (12, 30), IL-13 was a potent stimulator of tissue inflammation that caused a progressive increase in the accumulation of macrophages, lymphocytes, and eosinophils in the tissues and BAL fluids of IL-13 Tg+ mice with normal IL-11Rα loci. In the absence of IL-11Rα, an impressive decrease in this inflammatory response was noted. In 2- and 4-mo-old mice, impressive decreases in BAL total cell, macrophage, and eosinophil recovery were noted (Fig. 2, A and B). A similarly, impressive decrease in tissue inflammatory cell accumulation was apparent (Fig. 2,C and data not shown). In BAL and tissues, compensatory increases in neutrophils were not noted (Fig. 2).

FIGURE 2.

Role of IL-11Rα in IL-13-induced inflammation. A and B, The BAL cell recoveries of Tg/IL-11Rα+/+ mice (□), Tg/IL-11Rα−/− mice (▦), Tg+/IL-11Rα +/+ mice (▪), and Tg+/IL-11Rα −/− mice (▥) at 2 (A) and 4 (B) mo of age are compared. The histologic effects in 4-mo-old mice are illustrated in C (original magnification, ×10). ∗, p < 0.01.

FIGURE 2.

Role of IL-11Rα in IL-13-induced inflammation. A and B, The BAL cell recoveries of Tg/IL-11Rα+/+ mice (□), Tg/IL-11Rα−/− mice (▦), Tg+/IL-11Rα +/+ mice (▪), and Tg+/IL-11Rα −/− mice (▥) at 2 (A) and 4 (B) mo of age are compared. The histologic effects in 4-mo-old mice are illustrated in C (original magnification, ×10). ∗, p < 0.01.

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Previous studies from our laboratory demonstrated that IL-13 induces its tissue alterations in part via the induction of a wide array of CC chemokines (12). To investigate the mechanism by which IL-11Rα deficiency diminished IL-13-induced inflammation, we compared the expression of selected chemokines in IL-13 Tg+ mice with WT and null IL-11Rα loci. In Tg mice with WT or null IL-11Rα loci, the levels of mRNA encoding MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MIP-1α/CCL-3, MIP-1β/CCL4, MIP-2/CXCL-2/3, MIP-3α/CCL20, C10/CCL-6, eotaxin/CCL-11, eotaxin-2/CCL21, and thymus and activation-regulated chemokine (TARC)/CCL17 were comparable and in many cases were near or below the limits of detection of our assays (Fig. 3,A). As previously reported (12, 37), IL-13 increased the levels of mRNA encoding these chemokine moieties in Tg+ mice with WT IL-11Rα loci (Fig. 3,A). In contrast, in the absence of IL-11Rα, the ability of IL-13 to induce MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MIP-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2–3, MIP-3α/CCL20, C10/CCL6, eotaxin/CCL11, eotaxin-2/CCL21, and TARC/CCL17 was markedly diminished (Fig. 3,A). In accord with these mRNA alterations, comparable alterations in BAL MCP-1/CCL2, MIP-1α/CCL-3, and eotaxin/CCL-11 protein were observed (Fig. 3, B–D). Thus, IL-11Rα plays an essential role in the stimulation of selected chemokines by IL-13.

FIGURE 3.

Role of IL-11Rα in IL-13-induced chemokine stimulation. A, Comparison of the levels of mRNA encoding the noted chemokines in lungs from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. B–D, Levels of MCP-1, MIP-1α, and eotaxin protein were assessed by ELISA in BAL fluids from 2-mo-old (▦) and 4-mo-old (▪) mice. The evaluations in A are representative of four similar evaluations. B–D, Each value is the mean ± SEM of evaluations in a minimum of five mice. ∗, p < 0.05; ∗∗, p < 0.01.

FIGURE 3.

Role of IL-11Rα in IL-13-induced chemokine stimulation. A, Comparison of the levels of mRNA encoding the noted chemokines in lungs from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. B–D, Levels of MCP-1, MIP-1α, and eotaxin protein were assessed by ELISA in BAL fluids from 2-mo-old (▦) and 4-mo-old (▪) mice. The evaluations in A are representative of four similar evaluations. B–D, Each value is the mean ± SEM of evaluations in a minimum of five mice. ∗, p < 0.05; ∗∗, p < 0.01.

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Quantitative morphometric, biochemical, and immunohistochemical approaches were used to define the role of IL-11Rα in IL-13-induced pulmonary fibrosis and HA and myofibroblast accumulation. In these studies, we compared these collagen, HA, and cellular parameters in IL-13 Tg+ mice with WT and null IL-11Rα loci. Similar amounts of collagen and BAL HA and similar numbers of anti-smooth muscle actin-staining parenchymal cells were noted in lungs from WT littermate control mice and IL-11Rα−/− animals (Fig. 4). In WT mice, IL-13 caused an impressive increase in lung collagen content (Fig. 4, A and B) and BAL HA levels (Fig. 4,C) that could be easily determined by histochemical and biochemical measurement techniques. In addition, IL-13 increased the accumulation of parenchymal myofibroblast-like cells that contained anti-smooth muscle actin, but did not stain with Abs against smooth muscle myosin (Fig. 4,D and data not shown). In contrast, the levels of IL-13-induced collagen and HA were significantly reduced in lungs from Tg+ mice with null vs WT IL-11Rα loci (Fig. 4, A–C). Myofibroblast accumulation was similarly decreased in lungs from IL-13 Tg+/IL-11Rα−/− mice compared with Tg+/IL-11Rα+/+ animals (Fig. 4,D). Interestingly, the anti-smooth muscle actin staining of vascular smooth muscle cells was not altered in the absence of IL-11Rα (Fig. 4 D). Thus, IL-11 signaling plays a critical role in IL-13-induced tissue fibrosis and HA and myofibroblast accumulation.

FIGURE 4.

Role of IL-11Rα in IL-13-induced fibrosis and HA and myofibroblast accumulation. The collagen content of lungs from 4-mo-old IL-13 Tg and Tg+ mice with +/+ and −/− IL-11Rα loci were compared using Picosirius Red (A) and Sirchol (B) collagen evaluations. C, HA content of BAL fluids from Tg and Tg+ mice with WT and null IL-11Rα loci. D, Comparison of α-smooth muscle actin staining of lungs from 4-mo-old IL-13 Tg+ mice with +/+ and −/− IL-11Rα loci. A–C, Each value represents the mean ± SEM of evaluations in a minimum of five mice. D, Representative of four similar evaluations. ∗, p < 0.05; ∗∗, p < 0.01. N.D., none detected.

FIGURE 4.

Role of IL-11Rα in IL-13-induced fibrosis and HA and myofibroblast accumulation. The collagen content of lungs from 4-mo-old IL-13 Tg and Tg+ mice with +/+ and −/− IL-11Rα loci were compared using Picosirius Red (A) and Sirchol (B) collagen evaluations. C, HA content of BAL fluids from Tg and Tg+ mice with WT and null IL-11Rα loci. D, Comparison of α-smooth muscle actin staining of lungs from 4-mo-old IL-13 Tg+ mice with +/+ and −/− IL-11Rα loci. A–C, Each value represents the mean ± SEM of evaluations in a minimum of five mice. D, Representative of four similar evaluations. ∗, p < 0.05; ∗∗, p < 0.01. N.D., none detected.

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Previous studies from our laboratory demonstrated that the fibrotic effects of IL-13 are mediated by its ability to induce and activate TGF-β1 and that this activation is mediated to a great extent by MMP-9 (15). To define the importance of IL-11Rα in these responses, we evaluated the TGF-β1 production of Tg+ mice with WT and null IL-11Rα loci. In mice with a WT IL-11Rα locus, IL-13 was a potent stimulator of the levels of mRNA encoding TGF-β1, TGF-β2, and TGF-β3 (Fig. 5,A). IL-13 also augmented MMP-9 mRNA accumulation (Fig. 5,A). In accord with these observations, IL-13 increased the levels of spontaneously activated and total TGF-β1 protein in BAL fluids from these animals (Fig. 5, B and C). In all cases, these inductive effects appeared to be IL-11Rα-dependent, because the levels of mRNA encoding TGF-β1, -β2, and -β3 and MMP-9 and the production and activation of TGF-β1 were significantly decreased in IL-11Rα-null mutant mice (Fig. 5). Thus, IL-13 stimulates and activates TGF-β1 and induces production of the TGF-β1 activator, MMP-9, via an IL-11Rα-dependent mechanism.

FIGURE 5.

Role of IL-11Rα in IL-13 stimulation of TGF-β moieties and MMP-9. Lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. The levels of mRNA encoding TGF-β moieties and MMP-9 were assessed by RT-PCR (A), and the levels of bioactive (B) and total (C) TGF-β1 were evaluated by ELISA. A, Representative of four similar evaluations. B and C, Values represent the mean ± SEM of evaluation in a minimum of five mice that were either 2 (▦) or 4 (▪) mo of age.

FIGURE 5.

Role of IL-11Rα in IL-13 stimulation of TGF-β moieties and MMP-9. Lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. The levels of mRNA encoding TGF-β moieties and MMP-9 were assessed by RT-PCR (A), and the levels of bioactive (B) and total (C) TGF-β1 were evaluated by ELISA. A, Representative of four similar evaluations. B and C, Values represent the mean ± SEM of evaluation in a minimum of five mice that were either 2 (▦) or 4 (▪) mo of age.

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To define the role(s) of IL-11Rα in the pathogenesis of IL-13-induced alveolar remodeling, we compared the alterations in lung volume and alveolar size in IL-13 Tg+ mice with WT and null IL-11Rα loci. In accord with previous observations (13), IL-13 caused an impressive increase in these parameters in lungs from mice with WT IL-11Rα loci (Fig. 6, A and B). In contrast, these effects of IL-13 were significantly diminished in mice with null IL-11Rα loci (Fig. 6, A and B). Thus, IL-11Rα plays a key role in this remodeling response.

FIGURE 6.

Role of IL-11Rα in IL-13-induced alveolar remodeling. Lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. A and B, Lungs were fixed to pressure, and lung volume (A) and chord length (B) were assessed. C, Levels of mRNA encoding the noted proteases and antiproteases were evaluated; representative of four similar evaluations. A and B, Values represent the mean ± SEM of evaluations in a minimum of five mice that were either 2 (▦) or 4 (▪) mo of age. ∗, p < 0.01.

FIGURE 6.

Role of IL-11Rα in IL-13-induced alveolar remodeling. Lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. A and B, Lungs were fixed to pressure, and lung volume (A) and chord length (B) were assessed. C, Levels of mRNA encoding the noted proteases and antiproteases were evaluated; representative of four similar evaluations. A and B, Values represent the mean ± SEM of evaluations in a minimum of five mice that were either 2 (▦) or 4 (▪) mo of age. ∗, p < 0.01.

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To determine whether a deficiency of IL-11Rα could modulate the IL-13-induced alveolar phenotype by decreasing the production of respiratory proteases, we compared the levels of mRNA encoding lung-relevant MMPs and cathepsins in WT and IL-11Rα−/− mice. As noted above (Fig. 5,A), IL-13 is a potent stimulator of MMP-9, and this inductive event was mediated via an IL-11Rα-dependent pathway. As shown in Fig. 6,C, IL-13 was also a potent stimulator of MMP-2, MMP-12, tissue inhibitor of MMP (Timp)-1, Timp-2, Timp-3, Timp-4, cathepsin K, cathepsin S, cathepsin B, and cathepsin L. Interestingly, the induction of MMP-2, MMP-12, Timp-1 to -4, cathepsin K, and cathepsin B was decreased in the absence of IL-11Rα (Fig. 6 C). Thus, in the setting of a deficiency of IL-11Rα, IL-13 is unable to optimally stimulate lung proteases.

Studies were next undertaken to determine whether IL-11Rα played an important role in the pathogenesis of IL-13-induced mucus metaplasia. In these studies we compared mucin gene expression in Tg+ mice with WT and null IL-11Rα loci. The expression of gob-5, a calcium-activated chloride channel involved in the mucus response (38), was also evaluated. In lungs from Tg mice with WT or null IL-11Rα loci, the levels of expression of Muc-5ac and gob-5 were at or near the limits of detection in our assay (Fig. 7). In contrast, IL-13 was a potent stimulator of muc-5AC and gob-5 in murine lung (Fig. 7). Interestingly, the stimulation of muc5AC and gob-5 gene expression were diminished in Tg+ mice with null mutant IL-11Rα loci (Fig. 7). These studies demonstrate that IL-11 plays an important role in the pathogenesis of IL-13 stimulation of mucin and gob-5 gene expression.

FIGURE 7.

Role of IL-11Rα in IL-13 stimulation of mucin and gob-5 gene expression. Lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. The levels of mRNA encoding MUC-5ac and gob-5 were then evaluated. This experiment is representative of four similar evaluations.

FIGURE 7.

Role of IL-11Rα in IL-13 stimulation of mucin and gob-5 gene expression. Lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. The levels of mRNA encoding MUC-5ac and gob-5 were then evaluated. This experiment is representative of four similar evaluations.

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In CC10-IL-13 Tg+ mice, progressive lung pathology is noted. As a result, these mice die prematurely from a fibrodestructive, inflammatory alveolar filling process that abrogates normal respiratory function (12). To define the role of IL-11Rα in this fatal response, we compared the survival of IL-13 Tg+ mice with WT and null IL-11Rα loci. Tg+ mice with IL-11Rα+/+ loci started to die at ∼100 days of age, and 100% of these animals were dead by 4.1 mo of age (Fig. 8). As shown in Fig. 8, a deficiency of IL-11Rα significantly improved the survival of these animals, with Tg+/IL-11Rα−/− animals beginning to die at ∼5.5 mo of age and many animals living to 7.8 mo of age (Fig. 8). Thus, IL-11Rα plays a critical role in the pathogenesis of the IL-13-induced pathologies that lead to the death of these animals.

FIGURE 8.

Role of IL-11Rα in IL-13-induced respiratory failure and death. The figure compares the survival of Tg/IL-11Rα+/+ mice (○), Tg/IL-11Rα−/− mice (□), Tg+/IL-11Rα+/+ mice (•), and Tg+/IL-11Rα−/− mice (▪). Each value represents the survival of a minimum of eight mice. The survivals of Tg mice with +/+ and −/− loci are superimposed on one another. ∗, p < 0.05.

FIGURE 8.

Role of IL-11Rα in IL-13-induced respiratory failure and death. The figure compares the survival of Tg/IL-11Rα+/+ mice (○), Tg/IL-11Rα−/− mice (□), Tg+/IL-11Rα+/+ mice (•), and Tg+/IL-11Rα−/− mice (▪). Each value represents the survival of a minimum of eight mice. The survivals of Tg mice with +/+ and −/− loci are superimposed on one another. ∗, p < 0.05.

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Previous studies from our laboratory demonstrated that IL-13 confers an impressive level of cytoprotection in the context of hyperoxia-induced acute lung injury (19). To define the role of IL-11Rα in this protective response, we compared the survival of Tg+ and Tg mice with WT and null IL-11Rα loci in 100% O2. WT mice died after 4–6 days of exposure to 100% O2 (Fig. 9). Interestingly, IL-11Ra−/− mice were more susceptible to 100% O2 than their WT littermate controls, dying after 2–3 days of exposure to 100% O2. As described previously (36), IL-13 Tg+ mice with WT IL-11Rα loci lived for an extended interval, with many of these animals living for 8–12 days in hyperoxia (Fig. 9). Interestingly, a deficiency of IL-11Rα did not significantly alter this protective response (Fig. 9). Together, these studies demonstrate that IL-11Rα plays an important role in regulating the response of otherwise normal mice to hyperoxia. They also demonstrate that IL-11Rα does not play a significant role in the cytoprotection that is conferred by IL-13.

FIGURE 9.

Role of IL-11Rα in IL-13-induced cytoprotection in hyperoxia. Tg and Tg+ mice with +/+ and −/− IL-11Rα loci were placed in room air or in 100% O2, and survival was assessed. The figure compares the survival of Tg/IL-11Rα+/+ mice (○), Tg)/IL-11Rα−/− mice (□), Tg+/IL-11Rα+/+ mice (•), and Tg+/IL-11Rα−/− mice (▪). Each value represents the survival of a minimum of five mice. ∗, p < 0.05.

FIGURE 9.

Role of IL-11Rα in IL-13-induced cytoprotection in hyperoxia. Tg and Tg+ mice with +/+ and −/− IL-11Rα loci were placed in room air or in 100% O2, and survival was assessed. The figure compares the survival of Tg/IL-11Rα+/+ mice (○), Tg)/IL-11Rα−/− mice (□), Tg+/IL-11Rα+/+ mice (•), and Tg+/IL-11Rα−/− mice (▪). Each value represents the survival of a minimum of five mice. ∗, p < 0.05.

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A deficiency of IL-11Rα could modify the IL-13-induced phenotype by altering IL-13 production or the expression of the subunits that make up the IL-13R. To address the former, we compared the levels of IL-13 in BAL from Tg+ mice with WT and null IL-11Rα loci. As shown in Fig. 10,A, a deficiency of IL-11Rα did not alter the levels of transgenic IL-13 protein. To address the receptor issue, we compared the levels of expression of IL-4Rα and IL-13Rα1, which make up the signaling IL-13R complex, and the decoy receptor IL-13Rα2 in mice with WT and null IL-11Rα loci. The levels of mRNA encoding IL-4Rα, IL-13Rα1, and IL-13 Rα2 in Tg mice with WT and null IL-11Rα loci were comparable and were at or below the limits of detection of our assays (Fig. 10,B). As previously reported (39), IL-13 was a potent stimulator of each of these moieties (Fig. 10,B). In these experiments a deficiency of IL-11Rα caused only modest alterations in the levels of expression of IL-4Rα and IL-13Rα1 (Fig. 10,B). Importantly, in the absence of IL-11Rα, the levels of expression of IL-13Rα2 were not augmented (Fig. 10 B). In fact, modest decreases in the levels of expression of this decoy receptor were noted. These studies demonstrate that the amelioration of the IL-13 phenotype that is seen in IL-11Rα-null mice is not due to a decrease in IL-13 production, a decrease in IL-13Rα1-IL-4Rα receptor expression, or an increase in expression of the IL-13Rα2 decoy receptor.

FIGURE 10.

IL-11Rα regulation of BAL IL-13 and IL-13R subunit expression. BAL fluids and lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. The levels of BAL IL-13 (A) and mRNA encoding IL-13R subunits (B) were evaluated. B, Representative of four similar evaluations. The values in A represent the mean ± SEM of evaluations in a minimum of five mice that were 2 (▦) or 4 (▪) mo of age.

FIGURE 10.

IL-11Rα regulation of BAL IL-13 and IL-13R subunit expression. BAL fluids and lungs were obtained from Tg and Tg+ mice with +/+ and −/− IL-11Rα loci. The levels of BAL IL-13 (A) and mRNA encoding IL-13R subunits (B) were evaluated. B, Representative of four similar evaluations. The values in A represent the mean ± SEM of evaluations in a minimum of five mice that were 2 (▦) or 4 (▪) mo of age.

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Because IL-13 and IL-11 are juxtaposed in inflammatory tissues, studies were undertaken to define the relationship(s) between these important regulatory moieties. These studies demonstrate that IL-13 is potent stimulator of IL-11 and IL-11Rα. They also demonstrate that IL-13-induced inflammation, HA accumulation, myofibroblast accumulation, tissue fibrosis, alveolar remodeling, mucin gene expression, and respiratory failure and death were all diminished in IL-13 Tg mice with null mutations of IL-11Rα. Lastly they demonstrate that IL-13 is unable to optimally stimulate inflammatory chemokines, proteases, and mucin genes and is unable to fully stimulate and activate TGF-β1 in the absence of IL-11Rα. These studies define a previously unappreciated mechanism of regulation of IL-11 and IL-11Rα. Because IL-11 is the only known ligand for the IL-11Rα-gp130 receptor complex, these studies also define a previously unappreciated role for IL-11Rα, and presumably for IL-11, in the pathogenesis of IL-13-induced tissue responses.

IL-11 was discovered as an IL-6-like molecule that stimulated the proliferation of IL-6-dependent plasmacytoma cells (40). Subsequent investigation has focused to a great extent on the effects of exogenously administered rIL-11 and its role as a potential therapeutic agent. These studies highlighted impressive effects of IL-11 on platelets, which is the basis for the approval of IL-11 by the U.S. Food and Drug Administration as a treatment that fosters platelet reconstitution after bone marrow ablative therapy (17, 18). They also defined the ability of recombinant and transgenic IL-11 to confer cytoprotection and inhibit inflammation during states of mucosal/tissue injury (27, 28, 33, 41, 42, 43). These studies did not, however, address in detail the roles of endogenous IL-11 and IL-11 signaling in the generation of tissue inflammatory and extraosseous remodeling responses. The present studies provide a new level of insight into the biology of IL-11 by demonstrating that in addition to the protective effects of high concentrations of exogenous IL-11, endogenous IL-11 has important proinflammatory effects at sites of IL-13-mediated tissue inflammation. In the absence of IL-11 signaling, the ability of IL-13 to induce lymphocytic and eosinophilic tissue inflammation was markedly diminished. In accord with these findings, in the absence of IL-11Rα, IL-13 was also unable to optimally stimulate the production of the proinflammatory chemokines (MCP-1/CCL-2, MCP-2/CCL8, MCP-3/CCL7, MIP-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2–3, MIP-3α/CCL20, C10/CCL6, eotaxin/CCL11, eotaxin 2, and TARC/CCL17) that are known to play essential roles in the generation of IL-13-induced responses (12, 37). These are the first studies to demonstrate an important proinflammatory role for IL-11/IL-11Rα in Th2 inflammation and the first to demonstrate an important role for IL-11/IL-11Rα in the induction of Th2-focused chemokines. When combined with prior studies that demonstrate that exogenous IL-11 can prevent inflammation, the findings indicate that IL-11 has complex, context-specific effects on Th2 inflammation with the ability to augment and prevent these important responses. In many ways this is analogous to TGF-β, which can have similar bidirectional modulatory effects (44, 45, 46). This is an intriguing analogy, because work from our laboratory and others has demonstrated that IL-11 is potently induced by TGF-β1 in a variety of cells and tissues (18, 47, 48, 49).

Tissue fibrosis is a prominent feature of asthmatic airway remodeling and a major cause of morbidity and mortality in a variety of other pulmonary and extrapulmonary disorders. The Th2 cytokine hypothesis suggests that fibrosis is the result of Th2-dominated tissue inflammation and that IL-13 is the major mediator of these fibrotic responses (1, 6, 30, 50). We have previously demonstrated that IL-13 induces pulmonary fibrosis by inducing and activating TGF-β1 (15). We also demonstrated that this induction and activation are mediated at least in part by MCP-1/CCL2 and MMP-9, respectively (12, 15). The present studies add to our understanding of the pathogenesis of this important fibrogenic pathway by demonstrating that IL-11Rα plays a critical role in both responses. In the absence of IL-11Rα, the fibrotic effects of IL-13 were markedly diminished. In addition, the induction of MMP-9, the stimulation of MCP-1/CCL2, and the induction and activation of TGF-β1 were all markedly decreased. These observations in combination with previous reports from our laboratory demonstrating that TGF-β1 is a potent stimulator of IL-11 (18, 47, 48, 49) indicate an amplification pathway that can be activated in fibrotic tissues. During Th2 inflammation, IL-13 can stimulate IL-11 and IL-11Rα, which would, in turn, contribute to the induction of MCP-1/CCL2 and MMP-9. This would augment the production and activation of TGF-β1, which would feed back to further stimulate the production of IL-11. This amplification loop could contribute to the chronicity, progression, and/or severity of pulmonary and extrapulmonary fibrotic disorders.

Myofibroblasts are increasingly believed to play an essentially role in tissue fibrotic responses (51). Although their tissue source is still open to interpretation (52), their ability to accumulate and produce collagen and other matrix molecules at sites of injury and repair is now well accepted (51). It is also well known that myofibroblast accumulation and activation at sites of injury and repair are driven in part by TGF-β1 (45, 51). Our studies demonstrate that IL-13 induces myofibroblast accumulation and tissue fibrosis, and that IL-11Rα plays an essential role in these inductive events. These findings are in accord with previous studies from our laboratory that demonstrated that transgenic IL-11 causes pulmonary fibrosis and myofibroblast accumulation (53). Additional experimentation will be required to determine whether the inability to induce myofibroblast accumulation in the absence of IL-11Rα is the direct result of a defect in IL-11R signaling or the result of the important role that IL-11Rα plays in the induction and activation of TGF-β1.

In addition to its well-documented ability to induce eosinophilic inflammation, mucus metaplasia. and airway hyper-responsiveness (2, 3, 30), studies from our laboratory and others have also highlighted the ability of IL-13 to induce alveolar remodeling and alter protease/antiprotease balance in the lung (13). The later is the result of the ability of IL-13 to stimulate MMPs and cathepsins and inhibit α1 antitrypsin (13). Surprisingly the mechanisms of these inductive events have not been defined. The present studies address this issue by demonstrating that IL-11Rα (and presumably IL-11) play essential roles in the ability of IL-13 to cause alveolar enlargement and induce MMPs and cathepsins, because all three were decreased in IL-13 transgenic mice that were deficient in IL-11Rα. Previous studies from our laboratory also demonstrated that IL-11 has the ability to cause alveolar enlargement by blocking lung growth and development (54). When combined with the present studies, it is clear that IL-11 can alter alveolar structure via developmental and nondevelopmental pathways. The development-dependent alterations are particularly relevant to the alveolar enlargement that is seen in pediatric patients with bronchopulmonary dysplasia (55). In contrast, the development-independent effects have interesting implications with regard to the pathogenesis of pulmonary emphysema and chronic obstructive pulmonary disease. This is particularly intriguing because the subepithelial fibrosis and B cell- and T cell-rich nodules that have recently been described in tissues from patients with advanced COPD (56) are similar in many ways to subepithelial fibrotic response and B cell- and T cell-rich nodules described by our laboratory in IL-11 transgenic mice (53). In addition, polymorphisms in IL-11 have recently been shown to be associated with the development of COPD (57). These findings also have important implications for other diseases, such as periodontitis, idiopathic pulmonary fibrosis, scleroderma, and hepatic fibrosis, in which protease alterations and the exaggerated production of IL-13 or IL-11 have been noted (1, 5, 6, 7, 8, 9, 10, 11, 58).

The ability to induce goblet cell hypertrophy and mucus metaplasia is one of the most potent airway effects of IL-13 (59). Despite this potency, the mechanism of this response is poorly understood. It is clear, however, that IL-13 induces mucus metaplasia via a different mechanism than inflammation and fibrosis. This can be readily appreciated in studies that demonstrate that mucus metaplasia is not altered, whereas inflammation and fibrosis are decreased by interventions that ablate and/or neutralize specific chemokines, chemokine receptors, or TGF-β1 (12, 15, 37). An interesting feature in our studies is the demonstration that in the absence of IL-11Rα, the ability of IL-13 to stimulate mucin genes is significantly decreased. This is the first manipulation of IL-13 in vivo that simultaneously alters inflammation, fibrosis, and mucus responses. These studies demonstrate that IL-11Rα plays an important role in the pathogenesis of IL-13-induced mucus alterations. It is important to point out, however, that the role of IL-11Rα in mucus metaplasia is likely to be quite complex, because the overexpression of IL-11 by itself did not induce mucus metaplasia in the murine airway (53). Thus, IL-11Rα signaling plays an important role in IL-13 stimulation of mucin genes, but is not sufficient for the induction of airway mucus metaplasia.

In our studies the ability of IL-13 to induce inflammation, fibrosis, HA accumulation, alveolar remodeling, and respiratory failure and death was decreased in mice that were deficient in IL-11Rα. These alterations could be the result of a decrease in the production of transgenic IL-13, a decrease in IL-13 signaling, or a decrease in IL-13 effector pathway activation. The first two options are not likely, because similar levels of BAL IL-13 and similar levels of expression of the decoy receptor IL-13Rα2 were seen in mice with wild-type and null IL-11Rα loci. Additional support comes from the specificity of the alterations that were noted, because IL-13-induced cytoprotection in hyperoxia was not altered in IL-11Rα-deficient animals. The decrease in IL-13 effector pathway activation could be caused by at least two mechanisms. First, IL-11 could be an important target of and mediator of the tissue effects of IL-13. Alternatively, IL-11 could regulate the survival of critical IL-13 target cells that are involved in the pathogenesis of IL-13-induced inflammation, remodeling, and cytokine, protease, and matrix responses. Regardless, exaggerated IL-13 production has been implicated in the pathogenesis of a variety of disorders, including asthma, COPD, pulmonary fibrosis, scleroderma, hepatic fibrosis, and nodular sclerosing Hodgkin’s disease (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). The present studies suggest that the effector responses of IL-13 in these disorders may be beneficially controlled by interventions that block IL-11Rα and/or IL-11. This establishes the IL-11-IL-11Rα pathway as a worthwhile site for investigations designed to identify therapeutic agents that can be used to treat these and other IL-13-mediated disorders.

We thank Kathleen Bertier, Susan Ardito, and Karen D’Angelo for their excellent secretarial and administrative assistance and Drs. Lorraine Robb and C. Glenn Begley for the gift of the IL-11Rα-null mice.

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.

1

This work was supported by National Institutes of Health Grants HL64242, HL78744, HL66571, and HL56389 (to J.A.E.).

4

Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; BAL, bronchoalveolar lavage; HA, hyaluronic acid; MMP, matrix metalloproteinase; Tg, transgenic; Timp, tissue inhibitor of MMP; WT, wild type; TARC, thymus and activation-regulated chemokine.

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