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

IL-13 can bind to two distinct receptors: a heterodimer of IL-13R alpha 1/IL-4Ra alpha and IL-13R alpha 2. Whereas IL-13R alpha 1/IL-4R alpha engagement by IL-13 leads to the activation of STAT6, the molecular events triggered by IL-13 binding to IL-13R alpha 2 remain incompletely understood. IL-4 can bind to and signal through the IL-13R alpha 1/IL-4R alpha complex but does not interact with IL-13R alpha 2. 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-13R alpha 2, 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-13R alpha 2 expression can be induced in lung fibroblasts by IL-4 or IL-13 via a STAT6-dependent mechanism, or by TNF-alpha via a STAT6-independent mechanism. Endogenously expressed IL-13R alpha 2 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-13R alpha 1/IL-4R alpha or IL-13R alpha 2 show that endogenously expressed IL-13R alpha 2 does not activate any unique IL-13-mediated gene expression patterns, confirming its role as a decoy receptor for IL-13 signaling.