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Endogenously expressed IL-13Ralpha2 attenuates IL-13- mediated responses but does not activate signaling in human lung fibroblasts

Chandriani, S, DePianto, DJ, N'Diaye, EN, Abbas, AR, Jackman, J, Bevers, IJ, Ramirez-Carrozzi, V, Pappu, R, Kauder, SE, Toy, K, Ha, C, Modrusan, Z, Wu, LC, Collard, HR, Wolters, PJ, Egen, JG and Arron, JR (2014) Endogenously expressed IL-13Ralpha2 attenuates IL-13- mediated responses but does not activate signaling in human lung fibroblasts. Journal of Immunology. pp. 111-119.


IL-13 can bind to two distinct receptors: a heterodimer of IL-13Ralpha1/IL-4Ra and IL-13Ralpha2. Whereas IL-13Ralpha1/IL-4Ralpha engagement by IL-13 leads to the activation of STAT6, the molecular events triggered by IL-13 binding to IL-13Ralpha2 remain incompletely understood. IL-4 can bind to and signal through the IL-13Ralpha1/IL-4Ralpha complex but does not interact with IL-13Ralpha2. 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-13Ralpha2, 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-13Ralpha2 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-13Ralpha2 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-13Ralpha1/IL-4Ralpha or IL-13Ralpha2 show that endogenously expressed IL-13Ralpha2 does not activate any unique IL-13-mediated gene expression patterns, confirming its role as a decoy receptor for IL-13 signaling. Copyright 2014 by The American Association of Immunologists, Inc. All rights reserved

Item Type: Article
Additional Information: NIBR author: institute: NIBR contributor address: (Chandriani, DePianto, N'Diaye, Abbas, Jackman, Bevers III, Ramirez-Carrozzi, Pappu, Kauder, Toy, Ha, Modrusan, Wu, Egen, Arron) Genentech Research and Early Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States (Collard, Wolters) Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, United States (Chandriani) Novartis Institutes for Biomedical Research, Emeryville, CA, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12


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