title: 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.
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chandriani
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Daryle J
authors.initials: DJ
authors.lastname: DePianto
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Elsa N
authors.initials: EN
authors.lastname: N'Diaye
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Abbas
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Janet
authors.initials: J
authors.lastname: Jackman
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Jack
authors.initials: J
authors.lastname: Bevers
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ramirez-Carrozzi
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Rajita
authors.initials: R
authors.lastname: Pappu
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kauder
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Karen
authors.initials: K
authors.lastname: Toy
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Jackson G
authors.initials: JG
authors.lastname: Egen
authors.affiliation: Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and arron.joseph@gene.com.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
mesh_terms: D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology*; D055106:Genome-Wide Association Study; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology* / Q000473:pathology; D018793:Interleukin-13 / Q000276:immunology*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000276:immunology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C578095:IL13 protein, human; C508181:IL13RA1 protein, human; C508598:IL4 protein, human; C504000:IL4R protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053663:Interleukin-13 Receptor alpha2 Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4