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: Jennifer C Barnes, Robert V Lumsden, Julie Worrell, Ian P Counihan, Sarah L O'Beirne, John A Belperio, Aurelie Fabre, Seamas C Donnelly, Denise Boylan, Rosemary Kane, Michael P Keane
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 53 Issue 2 Pg. 217-25 (Aug 2015) ISSN: 1535-4989 [Electronic] United States
• PMID: 25514189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR3 protein, human
• IL13 protein, human
• Interleukin-13
• Interleukin-13 Receptor alpha2 Subunit
• Receptors, CXCR3

Topics

• Animals
• Cells, Cultured
• Female
• Fibroblasts (metabolism)
• Gene Expression
• Gene Expression Regulation
• Humans
• Idiopathic Pulmonary Fibrosis (metabolism, pathology)
• Interleukin-13 (physiology)
• Interleukin-13 Receptor alpha2 Subunit (genetics, metabolism)
• Lung (metabolism, pathology)
• Mice, Inbred BALB C
• Mice, Knockout
• Receptors, CXCR3 (physiology)
• Up-Regulation