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

Abstract

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.

Elevated protein arginine methyltransferase 1 expression regulates fibroblast motility in pulmonary fibrosis

“…In line with this notion, elevated levels of IL-4 were measured in IPF bronchial alveolar lavage fluid (BALF) and an increased expression of the IL-4 and IL-13 receptors was detected in IPF lung fibroblasts [5,6,7]. In addition, IL-4 deficient mice or mice with targeted disruption of the key components of the IL-4 signaling pathway were found to be protected against pulmonary fibrosis [8,9].…”

Mechanism of Periostin Production in Human Bronchial Smooth Muscle Cells

“…Using STAT6 knockout mice that were sensitized with house dust mites, a study demonstrated that STAT6 was a major transcription factor for producing periostin [20]. Furthermore, STAT6 siRNA decreased periostin expression in lung fibroblasts [24]. Subsequently, the ERK1/2 pathway, as well as the JAK/STAT6 pathway, has also been shown to be important for periostin production in human airway epithelial cells cultured at an air-liquid interface [25] and in human lung fibroblasts [26].…”

The cytokines of pulmonary fibrosis: Much learned, much more to learn

“…On the other hand, IL-13 first binds to the IL13Ra1 chain, leading to the recruitment of the IL-4Ra chain. Another chain, termed IL-13Ra2, also binds IL-13; there is an ongoing controversy as to whether IL-13Ra2 acts as a decoy receptor attenuating IL-13-driven fibrosis [154,155] or its triggering induces TGF-b, which in turn acts profibrotically [156,157]. Activation of the IL-4R complexes initiates complex intracellular signaling utilizing members of the JAK family of tyrosine kinases, the IRS family of proteins, STAT6, and other intracellular signaling mediators (reviewed in [153]).…”