Inhibition of Arginase I Activity by RNA Interference Attenuates IL-13-Induced Airways Hyperresponsiveness

Yang, Ming; Rangasamy, Danny; Matthaei, Klaus I.; Frew, Ailsa J.; Zimmmermann, Nives; Mahalingam, Suresh; Webb, Dianne C.; Tremethick, David J.; Thompson, Philip J.; Hogan, Simon P.; Rothenberg, Marc E.; Cowden, W. B.; Foster, Paul S.

doi:10.4049/jimmunol.177.8.5595

Cited by 88 publications

(94 citation statements)

References 64 publications

(70 reference statements)

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“…Quantitative PCR was performed as previously described (38). Briefly, RNA was prepared from cells or tissue using the TRIzol RNA isolation buffer following the manufacturer's instructions (Invitrogen).…”

Section: Quantitative Pcrmentioning

confidence: 99%

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

Wang

Baines

et al. 2010

The Journal of Immunology

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131

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Inflammation and airway hyperresponsiveness (AHR) are hallmark features of asthma and often correlate with the severity of clinical disease. Although these features of asthma can be effectively managed with glucocorticoid therapy, a subgroup of patients, typically with severe asthma, remains refractory to therapy. The mechanisms leading to steroid resistance in severe asthmatics are poorly understood but may be related to the activation of innate host defense pathways. Previously, we have shown that IFN-γ–producing cells and LPS, two factors that are associated with severe asthma, induce steroid-resistant AHR in a mouse model. We now demonstrate that cooperative signaling induced by IFN-γ and LPS results in the production of IL-27 by mouse pulmonary macrophages. IL-27 and IFN-γ uniquely cooperate to induce glucocorticoid-resistant AHR through a previously unknown MyD88-dependent mechanism in pulmonary macrophages. Importantly, integrated signaling by IL-27/IFN-γ inhibits glucocorticoid-induced translocation of the glucocorticoid receptor to the nucleus of macrophages. Furthermore, expression of both IL-27 and IFN-γ was increased in the induced sputum of steroid-refractory asthmatics. These results suggest that a potential mechanism for steroid resistance in asthma is the activation of MyD88-dependent pathways in macrophages that are triggered by IL-27 and IFN-γ, and that manipulation of these pathways may be a therapeutic target.

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Section: Quantitative Pcrmentioning

confidence: 99%

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

Wang

Baines

et al. 2010

The Journal of Immunology

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131

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“…Airway reactivity (resistance: Raw) was measured using a modification of the low-frequency forced oscillation technique as previously described (21). Briefly, once mice were stably anesthetized, they were challenged with a saline aerosol followed by increasing concentrations of ␤-methacholine (5, 10, 20, and 40 mg/ml; Sigma-Aldrich).…”

Section: Measurement Of Airway Resistancementioning

confidence: 99%

“…The numbers of neutrophils and eosinophils in the BALF were identified by morphologic criteria as previously described (21).…”

Section: Characterization Of Lung Morphology and Bronchoalveolar Lavagementioning

confidence: 99%

Pathogenesis of Steroid-Resistant Airway Hyperresponsiveness: Interaction between IFN-γ and TLR4/MyD88 Pathways

Yang

Kumar

Foster

2009

The Journal of Immunology

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110

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Chronic inflammation and airway hyperresponsiveness (AHR) in asthmatics are usually managed effectively by treatment with glucocorticoids. However, a subset of patients remains refractory to therapy. The underlying mechanisms are largely unknown, although recruitment of neutrophils (rather than eosinophils) is strongly correlated, suggesting a role for nonallergic host defense responses. Increased levels of IFN-γ and endotoxins are also related to severe asthma and because these activate host defense pathways, we investigated a possible common etiologic link to steroid-resistant disease. To be able to unravel the complexity of asthmatic inflammation, we used two model systems which permitted dissection of the relevant molecular pathways. In the first of these, we transferred transgenic OVA323–339 peptide-specific IFN-γ-producing Th1 cells into mice. These animals were subsequently challenge via the airways with OVA323–339 peptide and/or LPS. Challenge with both components, but not with either one individually, induced AHR. Importantly, AHR was resistant to treatment with dexamethasone. Development of AHR was dependent on IFN-γ, inhibited by depletion of pulmonary macrophages (but not neutrophils) and abrogated in TLR4- or MyD88-deficient mice. In contrast, in the second model in which we transferred OVA323–339 peptide-activated Th2 cells, eosinophilic inflammation and AHR were induced, and both were suppressed by steroid treatment. We conclude that cooperative signaling between IFN-γ and TLR4/MyD88 constitutes a previously unrecognized pathway that regulates macrophage-dependent steroid-resistant AHR.

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“…The identification of arginase 1 from array studies in a mouse model led to identification of increased arginase in lung tissue from human asthmatics as well (13). Following initial identification by array analysis, continued studies have begun a more detailed analysis of the expression and regulation of some of these candidate genes in allergen or IL-13 induced inflammation and airway hyperresponsiveness in mouse models (14)(15)(16)(17). Rigorous experiments to implicate these molecules as critical to the allergen induced symptoms in mouse models of asthma have not yet been done.…”

Section: Use Of Microarrays To Identify Novel Effector Mechanismsmentioning

confidence: 99%

Mechanisms of occupational asthma: Not all allergens are equal

Regal

Greene

Regal

2007

Environ Health Prev Med

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Asthma is a heterogeneous lung disorder characterized by airway obstruction, inflammation and eosinophil infiltration into the lung. Both genetics and environmental factors influence the expression of asthma, and not all asthma is the result of a specific immune response to allergen. Numerous asthma phenotypes have been described, including occupational asthma, and therapeutic strategies for asthma control are similar regardless of phenotype. We hypothesized that mechanistic pathways leading to asthma symptoms in the effector phase of the disorder differ with the inciting allergen. Since route of allergen exposure can influence mechanistic pathways, mice were sensitized by identical routes with a high molecular weight occupational allergen ovalbumin and a low molecular weight occupational allergen trimellitic anhydride (TMA). Different statistical methods with varying selection criteria resulted in identification of similar candidate genes. Array data are intended to provide candidate genes for hypothesis generation and further experimentation. Continued studies focused on genes showing minimal changes in the TMA-induced model but with clear up-regulation in the ovalbumin model. Two of these genes, arginase 1 and eotaxin 1 are the focus of continuing investigations in mouse models of asthma regarding differences in mechanistic pathways depending on the allergen. Microarray data from the ovalbumin and TMA model of asthma were also compared to previous data using Aspergillus as allergen to identify putative asthma 'signature genes', i.e. genes up-regulated with all 3 allergens. Array studies provide candidate genes to identify common mechanistic pathways in the effector phase, as well as mechanistic pathways unique to individual allergens.

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Inhibition of Arginase I Activity by RNA Interference Attenuates IL-13-Induced Airways Hyperresponsiveness

Cited by 88 publications

References 64 publications

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

Pathogenesis of Steroid-Resistant Airway Hyperresponsiveness: Interaction between IFN-γ and TLR4/MyD88 Pathways

Mechanisms of occupational asthma: Not all allergens are equal

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