TNF-α and IL-4 regulate expression of IL-13 receptor α2 on human fibroblasts

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.

Section: Il-13ra2 Expression Is Induced By Il-13 and Tnf-a In Lung Fimentioning

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 inability of IL-13R␣2 expression to confer IL-13 responsiveness despite high affinity binding, along with the finding of soluble IL-13R␣2 in vivo (9), has led to speculation that IL-13R␣2 is a decoy receptor. Expression of IL-13R␣2 varies across cell types and can be induced by inflammation and cytokines (15)(16)(17)(18)(19)(20). A role for IL-13R␣2 as a potential modulator of inflammation in asthma is suggested by the IL-13-and IL-4-dependent up-regulation of IL-13R␣2 in primary bronchial epithelial cells and the demonstration that overexpression of IL-13R␣2 in bronchial derived cells decreases IL-13-dependent Stat6 phosphorylation (21).…”

Section: Level Of Expression Of Il-13r␣2 Impacts Receptormentioning

confidence: 99%

Level of Expression of IL-13Rα2 Impacts Receptor Distribution and IL-13 Signaling

Daines

Tabata

Walker

et al. 2006

IL-13, a critical cytokine for allergic inflammation, exerts its effects through a complex receptor system including IL-4Rα, IL-13Rα1, and IL-13Rα2. IL-4Rα and IL-13Rα1 form a heterodimeric signaling receptor for IL-13. In contrast, IL-13Rα2 binds IL-13 with high affinity but does not signal. IL-13Rα2 exists on the cell surface, intracellularly, and in soluble form, but no information is available regarding the relative distributions of IL-13Rα2 among these compartments, whether the compartments communicate, and how the relative expression levels impact IL-13 responses. Herein, we investigated the distribution of IL-13Rα2 in transfected and primary cells, and we evaluated how the total level of IL-13Rα2 expression impacted its distribution. Our results demonstrate that the distribution of IL-13Rα2 is independent of the overall level of expression. The majority of the IL-13Rα2 protein existed in intracellular pools. Surface IL-13Rα2 was continually released into the medium in a soluble form, yet surface expression remained constant supporting receptor trafficking to the cell surface. IL-13Rα2 inhibited IL-13 signaling proportionally to its level of expression, and this inhibition could be overcome with high concentrations of IL-13.

“…Described primarily as a decoy, IL-13Ra2 is a potent antagonist of IL-13 bioactivity mediated through the IL-13Ra1/IL-4Ra complex on human fibroblasts (5)(6)(7)(8), epithelial cells (9)(10)(11), keratinocytes (12,13), and smooth muscle cells (12,14,15). Recent reports suggested that IL-13Ra2 may have some signaling capacity, resulting in fibrotic responses to IL-13 (16).…”

mentioning

confidence: 99%

“…In humans, cell surface expression of IL-13Ra2 is highly regulated, and it is inducible on fibroblasts, smooth muscle cells, keratinocytes, and other cell types following exposure to IL-13, IL-4, TNF-a, IFN-g, or combinations of these cytokines (7,14,27). IL-13Ra2 efficiently mediates internalization of bound cytokine (28), and it was suggested that IL-13Ra2 mediates clearance of local IL-13 (29), although this has not been clearly demonstrated in vivo.…”

mentioning

confidence: 99%

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

Kasaian

Raible²,

Marquette

et al. 2011

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.