title: CXCR3 Requirement for the Interleukin-13-Mediated Up-Regulation of Interleukin-13Rα2 in Pulmonary Fibroblasts.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and abnormal vascularity. IL-13, a profibrotic cytokine that plays a role in IPF, functions through the Jak/STAT pathway after binding to the IL-13 receptor α1 (IL-13Rα1)/IL-4Rα complex. IL-13 also binds to IL-13Rα2, which has been thought to function as a nonsignaling decoy receptor, although possible signaling roles of this receptor have been proposed. CXCR3 and its IFN-inducible ligands-CXCL9, CXCL10, and CXCL11-have been implicated in vascular remodeling and fibroblast motility during the development of IPF. In this study, CXCR3 expression was demonstrated in cultured pulmonary fibroblasts from wild-type BALB/c mice and was found to be necessary for the IL-13-mediated gene and protein up-regulation of IL-13Rα2. In fibroblasts from CXCR3-deficient mice, STAT6 activation was prolonged. This study is the first to demonstrate the expression of CXCR3 in fibroblasts and its association with the expression of IL-13Rα2. Taken together, the results from this study point strongly to a requirement for CXCR3 for IL-13-mediated IL-13Rα2 gene expression. Understanding the function of CXCR3 in IL-13-mediated lung injury may lead to novel approaches to combat the development of pulmonary fibrosis, whether by limiting the effects of IL-13 or by manipulation of angiostatic pathways. The elucidation of the complex relationship between these antifibrotic receptors and manipulation of the CXCR3-mediated regulation of IL-13Rα2 may represent a novel therapeutic modality in cases of acute lung injury or chronic inflammation that may progress to fibrosis.
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Barnes
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Lumsden
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Julie
authors.initials: J
authors.lastname: Worrell
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Counihan
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: O'Beirne
authors.affiliation: 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and.
authors.forename: John A
authors.initials: JA
authors.lastname: Belperio
authors.affiliation: Departments of 3 Pathology and.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Fabre
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.|4 Respiratory Medicine, St. Vincent's University Hospital, Elm Park, Dublin, Ireland.
authors.forename: Seamas C
authors.initials: SC
authors.lastname: Donnelly
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Denise
authors.initials: D
authors.lastname: Boylan
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Kane
authors.affiliation: 1 UCD Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.|4 Respiratory Medicine, St. Vincent's University Hospital, Elm Park, Dublin, Ireland.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keane
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D018793:Interleukin-13 / Q000502:physiology*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054367:Receptors, CXCR3 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C515187:CXCR3 protein, human; C578095:IL13 protein, human; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D054367:Receptors, CXCR3
keywords: CXCR3; IL-13; IL-13Rα2; fibroblasts; idiopathic pulmonary fibrosis