IL-11 Selectively Inhibits Aeroallergen-Induced Pulmonary Eosinophilia and Th2 Cytokine Production

Wang, Jingming; Homer, Robert J.; Lin, Hong; Cohn, Lauren; Lee, Chang-Min; Jung, Sung‐Soo; Elias, Jack A.

doi:10.4049/jimmunol.165.4.2222

Cited by 61 publications

(46 citation statements)

References 50 publications

(48 reference statements)

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“…Bronchoalveolar Lavage (BAL)-Lung inflammation was assessed by BAL as described previously (6,27). The BAL samples from each animal were pooled and centrifuged.…”

Section: Methodsmentioning

confidence: 99%

Role of Early Growth Response-1 (Egr-1) in Interleukin-13-induced Inflammation and Remodeling

Cho

Kang

Homer

et al. 2006

Journal of Biological Chemistry

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IL-13 is an important stimulator of inflammation and tissue remodeling at sites of Th2 inflammation, which plays a key role in the pathogenesis of a variety of human disorders. We hypothesized that the ubiquitous transcription factor, early growth response-1 (Egr-1), plays a key role in IL-13-induced tissue responses. To test this hypothesis we compared the expression of Egr-1 and related moieties 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 Egr-1 on the tissue effects of transgenic IL-13. These studies demonstrate that IL-13 stimulates Egr-1 via an Erk1/2-independent Stat6-dependent pathway(s). They also demonstrate that IL-13 is a potent stimulator of eosinophil-and mononuclear cell-rich inflammation, alveolar remodeling, and tissue fibrosis in mice with wild type Egr-1 loci and that these alterations are ameliorated in the absence of Egr-1. Lastly, they provide insights into the mechanisms of these processes by demonstrating that IL-13 stimulates select CC and CXC chemokines (MIP-1␣/CCL-3, MIP-1␤/CCL-4, MIP-2/CXCL2/3, MCP-1/ CCL-2, MCP-2/CCL-8, MCP-3/CCL-7, MCP-5/CCL-12, KC/CXCL-1, and Lix/CXCL-5), matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and apoptosis regulators (caspase-3, -6, -8, and -9 and Bax) and activates transforming growth factor-␤ 1 and pulmonary caspases via Egr-1-dependent pathways. These studies demonstrate that Egr-1 plays a key role in the pathogenesis of IL-13-induced inflammatory and remodeling responses. Interleukin (IL2 )-13 is a 12-kDa product of a gene on chromosome 5q31 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 play distinct roles in biology with IL-4 contributing to Th2 cell differentiation and response generation, whereas IL-13 contributes as a major effector of Th2 inflammation and tissue remodeling (1-4). The latter is nicely illustrated in studies from our laboratory and others that demonstrate that IL-13 is a potent stimulator of eosinophil-, macrophage-and lymphocyte-rich inflammation, mucus metaplasia, tissue fibrosis, and parenchymal proteolysis (5-7). 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, scleroderma, idiopathic pulmonary fibrosis, viral pneumonia, hepatic fibrosis, nodular sclerosing Hodgkin's disease, and chronic obstructive pulmonary diseases (COPD) (1-4, 7-13). 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), transforming growth factor (TGF)-␤ 1 , and chitinases (6, 14 -17). ...

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“…Bronchoalveolar Lavage (BAL)-Lung inflammation was assessed by BAL as described previously (6,27). The BAL samples from each animal were pooled and centrifuged.…”

Section: Methodsmentioning

confidence: 99%

Role of Early Growth Response-1 (Egr-1) in Interleukin-13-induced Inflammation and Remodeling

Cho

Kang

Homer

et al. 2006

Journal of Biological Chemistry

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“…mRNA Analysis-mRNA levels were assessed using RT-PCR and ribonuclease protection assays (RPA) as previously described by our laboratory (38,39). In the RT-PCR assays, gene-specific primers were used to amplify selected regions of each target moiety.…”

Section: Methodsmentioning

confidence: 99%

“…Histologic Evaluation-Histologic evaluations of 10% formalin, pressure-fixed (25 cm) lungs, and formalin-fixed extrathoracic tissues were obtained as previously described (37)(38)(39) (10,20, and 30% in 0.1 M phosphate buffer, pH 7.4). The lungs were then inflated with a 40% optimal cutting temperature solution diluted in PBS; cryomolds were prepared with optimal cutting temperature; and 7-m tissue sections were prepared on microscopic glass slides, air-dried at room temperature, and stored at Ϫ80°C for further use.…”

Section: Methodsmentioning

confidence: 99%

Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways

Lee

Homer

Cohn

et al. 2002

Journal of Biological Chemistry

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143

115

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To address the complex chronic effector properties of interleukin (IL)-10, we generated transgenic mice in which IL-10 was overexpressed in the lung. In these mice, IL-10 inhibited endotoxin-induced tumor necrosis factor production and neutrophil accumulation. IL-10 also caused mucus metaplasia, B and T cell-rich inflammation, and subepithelial fibrosis and augmented the levels of mRNA encoding Gob-5, mucins, and IL-13. In mice bred to have null mutations of IL-13, IL-4R␣, or STAT-6, transgenic IL-10 did not induce mucus metaplasia but did induce inflammation and fibrosis. IL-10 was also a critical mucin regulator of virus-induced mucus metaplasia. Thus, IL-10, although inhibiting lipopolysaccharide-induced inflammation, also causes mucus metaplasia, tissue inflammation, and airway fibrosis. These responses are mediated by multiple mechanisms with mucus metaplasia being dependent on and the inflammation and fibrosis being independent of an IL-13/ IL-4R␣/STAT-6 activation pathway.

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“…Lung inflammation was assessed by bronchoalveolar lavage (BAL) as previously described (13,29). The BAL samples from each animal were then pooled and centrifuged.…”

Section: Bronchoalveolar Lavagementioning

confidence: 99%

“…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 (13,29). The supernatants were stored at Ϫ20°C until used.…”

Section: Bronchoalveolar Lavagementioning

confidence: 99%

IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

Zhu¹,

Ma²,

Zheng³

et al. 2002

The Journal of Immunology

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179

158

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IL-13 stimulates inflammatory and remodeling responses and contributes to the pathogenesis of human airways disorders. To further understand the cellular and molecular events that mediate these responses, we characterized the effects of IL-13 on monocyte chemotactic proteins (MCPs) and compared the tissue effects of transgenic IL-13 in mice with wild-type (+/+) and null (−/−) CCR2 loci. Transgenic IL-13 was a potent stimulator of MCP-1, -2, -3, and -5. This stimulation was not specific for MCPs because macrophage-inflammatory protein (MIP)-1α, MIP-1β, MIP-2, MIP-3α, thymus- and activation-regulated chemokine, thymus-expressed chemokine, eotaxin, eotaxin 2, macrophage-derived chemokines, and C10 were also induced. The ability of IL-13 to increase lung size, alveolar size, and lung compliance, to stimulate pulmonary inflammation, hyaluronic acid accumulation, and tissue fibrosis, and to cause respiratory failure and death were markedly decreased, whereas mucus metaplasia was not altered in CCR2−/− mice. CCR2 deficiency did not decrease the basal or IL-13-stimulated expression of target matrix metalloproteinases or cathepsins but did increase the levels of mRNA encoding α1-antitrypsin, tissue inhibitor of metalloproteinase-1, -2, and -4, and secretory leukocyte proteinase inhibitor. In addition, the levels of bioactive and total TGF-β1 were decreased in lavage fluids from IL-13 transgenic mice with −/− CCR2 loci. These studies demonstrate that IL-13 is a potent stimulator of MCPs and other CC chemokines and document the importance of MCP-CCR2 signaling in the pathogenesis of the IL-13-induced pulmonary phenotype.

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IL-11 Selectively Inhibits Aeroallergen-Induced Pulmonary Eosinophilia and Th2 Cytokine Production

Cited by 61 publications

References 50 publications

Role of Early Growth Response-1 (Egr-1) in Interleukin-13-induced Inflammation and Remodeling

Role of Early Growth Response-1 (Egr-1) in Interleukin-13-induced Inflammation and Remodeling

Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways

IL-13-Induced Chemokine Responses in the Lung: Role of CCR2 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling

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