IL-13 Receptor α2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung

Zheng, Tao; Liu, Wei; Oh, Sun Young; Zhu, Zhou; Hu, Buqu; Homer, Robert J.; Cohn, Lauren; Grusby, Michael J.; Elias, Jack A.

doi:10.4049/jimmunol.180.1.522

Cited by 74 publications

(56 citation statements)

References 63 publications

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“…The extracellular domain of IL-13Ra2, which binds IL-13, can function as a decoy to the IL-13Ra1/IL-4Ra receptor complex and attenuate STAT6-dependent IL-13 signals (19)(20)(21). We monitored dose responsiveness to IL-13 by measuring the transcript levels of known STAT6-responsive genes (periostin and CCL26) whose expression was not induced by TNF-a treatment in IMR90 and adult control and IPF lung fibroblasts (Fig.…”

Section: Tnf-a-mediated Il-13ra2 Induction Attenuates Il-13 Signalingmentioning

confidence: 99%

“…STAT6 signaling can contribute to lung fibrosis by inducing the expression of extracellular matrix proteins in fibroblasts and differentiation of macrophages into an alternatively activated phenotype (18). A second IL-13 receptor, IL-13Ra2, has been implicated as a nonsignaling decoy receptor that can compete for IL-13 binding to the IL-13Ra1/IL-4Ra complex, thereby reducing STAT6 activation (19)(20)(21). IL-13Ra2 can be induced by STAT6-dependent as well as STAT6-independent signals (22) and is expressed at elevated levels in fibrotic tissue.…”

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confidence: 99%

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Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Chandriani¹,

DePianto²,

N'Diaye³

et al. 2014

The Journal of Immunology

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IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Rα and IL-13Rα2. Whereas IL-13Rα1/IL-4Rα engagement by IL-13 leads to the activation of STAT6, the molecular events triggered by IL-13 binding to IL-13Rα2 remain incompletely understood. IL-4 can bind to and signal through the IL-13Rα1/IL-4Rα complex but does not interact with IL-13Rα2. Idiopathic pulmonary fibrosis is a progressive and generally fatal parenchymal lung disease of unknown etiology with no current pharmacologic treatment options that substantially prolong survival. Preclinical models of fibrotic diseases have implicated IL-13 activity on multiple cell types, including macrophages and fibroblasts, in initiating and perpetuating pathological fibrosis. In this study, we show that IL-13, IL-4, IL-13Rα2, and IL-13–inducible target genes are expressed at significantly elevated levels in lung tissue from patients with idiopathic pulmonary fibrosis compared with control lung tissue. IL-4 and IL-13 induce virtually identical transcriptional responses in human monocytes, macrophages, and lung fibroblasts. IL-13Rα2 expression can be induced in lung fibroblasts by IL-4 or IL-13 via a STAT6-dependent mechanism, or by TNF-α via a STAT6-independent mechanism. Endogenously expressed IL-13Rα2 decreases, but does not abolish, sensitivity of lung fibroblasts to IL-13 and does not affect sensitivity to IL-4. Genome-wide transcriptional analyses of lung fibroblasts stimulated with IL-13 in the presence of Abs that selectively block interactions of IL-13 with IL-13Rα1/IL-4Rα or IL-13Rα2 show that endogenously expressed IL-13Rα2 does not activate any unique IL-13–mediated gene expression patterns, confirming its role as a decoy receptor for IL-13 signaling.

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Section: Tnf-a-mediated Il-13ra2 Induction Attenuates Il-13 Signalingmentioning

confidence: 99%

mentioning

confidence: 99%

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Chandriani¹,

DePianto²,

N'Diaye³

et al. 2014

The Journal of Immunology

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“…Using a model of IL-13 transgenic mice, we saw that disruption of IL-13Ra2 in these mice led to significant augmentation of the IL-13-induced pulmonary inflammation, mucus metaplasia, subepithelial fibrosis and airway remodelling in the lung. 51 Similar disruption of IL-13Ra2 had no effect on the tissue effects of lung-targeted transgenic IL-4 mice. 51 In a parasitic helminth Th2 infection model, the use of IL-13Ra2 null mice showed marked exacerbation of fibrosis despite the fact that the levels of IL-13 were significantly decreased, highlighting the importance of this receptor in the down-regulation of a chronic and pathogenic Th2-mediated immune response.…”

Section: Cytokine Receptorsmentioning

confidence: 99%

“…51 Similar disruption of IL-13Ra2 had no effect on the tissue effects of lung-targeted transgenic IL-4 mice. 51 In a parasitic helminth Th2 infection model, the use of IL-13Ra2 null mice showed marked exacerbation of fibrosis despite the fact that the levels of IL-13 were significantly decreased, highlighting the importance of this receptor in the down-regulation of a chronic and pathogenic Th2-mediated immune response. 52 Interleukin-33 is a new member of the IL-1 family, and has been shown to be a ligand for the ST2L receptor, which is expressed mostly on mast cells, Th2 cells, basophils and eosinophils.…”

Section: Cytokine Receptorsmentioning

confidence: 99%

Transgenic modelling of cytokine polarization in the lung

et al. 2010

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SummaryThe lung is one of the commonest sites of exposure to environmental allergen or pathogen, so the expression of a variety of cytokines in the lung is dynamically regulated by inflammatory or structural cells in the lung. In the last decades, characterization of the local lung cytokine milieu in allergic or injury models has identified a collective role of certain cytokines, such as type 1 or type 2 cytokines, driving polarized inflammatory and tissue phenotypes. With the development of transgenic mouse modelling systems, the effector function of individual cytokine and the pathophysiological consequences of cytokine polarization in the lung have been effectively evaluated. Here, we present an overview of the transgenic systems currently used to assess the biological function of cytokine or other mediators in the lung. We discuss the inflammatory and tissue phenotypes detected in the lungs of transgenic mice over-expressing representative T helper type 1 (interferon-c, interleukin-12), T helper type 2 (interleukins -4, -5, -9, -10 and -13), and T helper type 17 cytokines. The effects of genetic modification of cytokine receptors or transcriptional factors such as GATA-3 and T-bet in pulmonary inflammation and remodelling tissue responses are also discussed because these transcription factors are regarded as essential regulators of cytokine polarization. Finally, we discuss the limitations and future application of transgenic approaches in the studies of human lung diseases characterized by cytokine polarization.

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“…Mice lacking IL-13Ra2 have high levels of IL-13 in tissues and display functional responses consistent with overexpression of IL-13, as would be expected from lack of decoy activity (22)(23)(24). They also have reduced titers of circulating IL-13 (22), suggesting that the soluble form of IL-13Ra2 could act as a carrier or chaperone for IL-13 in the circulation.…”

mentioning

confidence: 94%

IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2

Kasaian

Raible²,

Marquette

et al. 2011

The Journal of Immunology

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Human studies using Abs to two different, nonoverlapping epitopes of IL-13 suggested that epitope specificity can have a clinically significant impact on clearance of IL-13. We propose that Ab modulation of IL-13 interaction with IL-13Rα2 underlies this effect. Two Abs were administered to healthy subjects and mild asthmatics in separate dose-ranging studies and allergen-challenge studies. IMA-638 allows IL-13 interaction with IL-13Rα1 or IL-13Rα2 but blocks recruitment of IL-4Rα to the IL-13/IL-13Rα1 complex, whereas IMA-026 competes with IL-13 interaction with IL-13Rα1 and IL-13Rα2. We found ∼10-fold higher circulating titer of captured IL-13 in subjects treated with IMA-026 compared with those administered IMA-638. To understand how this difference could be related to epitope, we asked whether either Ab affects IL-13 internalization through cell surface IL-13Rα2. Humans inducibly express cell surface IL-13Rα2 but lack the soluble form that regulates IL-13 responses in mice. Cells with high IL-13Rα2 expression rapidly and efficiently depleted extracellular IL-13, and this activity persisted in the presence of IMA-638 but not IMA-026. The potency and efficiency of this clearance pathway suggest that cell surface IL-13Rα2 acts as a scavenger for IL-13. These findings could have important implications for the design and characterization of IL-13 antagonists.

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IL-13 Receptor α2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung

Cited by 74 publications

References 63 publications

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Transgenic modelling of cytokine polarization in the lung

IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2

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