TY - JOUR
T1 - Endogenously expressed IL-13Rα2 attenuates IL-13- mediated responses but does not activate signaling in human lung fibroblasts
AU - Chandriani, Sanjay
AU - DePianto, Daryle J.
AU - N'Diaye, Elsa N.
AU - Abbas, Alexander R.
AU - Jackman, Janet
AU - Bevers, Jack
AU - Ramirez-Carrozzi, Vladimir
AU - Pappu, Rajita
AU - Kauder, Steven E.
AU - Toy, Karen
AU - Ha, Connie
AU - Modrusan, Zora
AU - Wu, Lawren C.
AU - Collard, Harold R.
AU - Wolters, Paul J.
AU - Egen, Jackson G.
AU - Arron, Joseph R.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Ra 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.
AB - IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Ra 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.
UR - http://www.scopus.com/inward/record.url?scp=84903626965&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903626965&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1301761
DO - 10.4049/jimmunol.1301761
M3 - Article
C2 - 24879793
AN - SCOPUS:84903626965
SN - 0022-1767
VL - 193
SP - 111
EP - 119
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -