Transcriptional regulation of the IL-13Rα2 gene in human lung fibroblasts

• Published in: Scientific reports Vol. 10; no. 1; p. 1083
• Main Authors: Penke, Loka R., Ouchi, Hideyasu, Speth, Jennifer M., Lugogo, Njira, Huang, Yvonne J., Huang, Steven K., Peters-Golden, Marc
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.01.2020; Nature Publishing Group
• Subjects: 631/250/127/1213; 631/337/572/2102; 631/80/86/2365; 631/80/86/2368; AKT protein; Allergic diseases; Asthma; Cyclic AMP response element-binding protein; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytokines; Dinoprostone - metabolism; Fibroblast growth factor 2; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Gene Expression Regulation; Gene regulation; Humanities and Social Sciences; Humans; Interleukin 13; Interleukin-13 - genetics; Interleukin-13 - metabolism; Interleukin-13 Receptor alpha2 Subunit - genetics; Interleukin-13 Receptor alpha2 Subunit - metabolism; Kinases; Lung - cytology; Lung - metabolism; multidisciplinary; Prostaglandin E2; Protein kinase A; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Science; Science (multidisciplinary); Signal Transduction; Transcription; Transcription, Genetic
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-57972-1

Interleukin (IL)−13 is a type 2 cytokine with important roles in allergic diseases, asthma, and tissue fibrosis. Its receptor (R) α1 is primarily responsible for the biological actions of this cytokine, while Rα2 possesses a decoy function which can block IL-13 signaling. Although the expression of Rα2 is known to be subject to modulation, information about its transcriptional regulation is limited. In this study, we sought to expand the understanding of transcriptional control of Rα2 in lung fibroblasts. We confirmed previous reports that IL-13 elicited modest induction of Rα2 in normal adult human lung fibroblasts, but found that prostaglandin E 2 (PGE 2 ) and fibroblast growth factor 2 (FGF-2) –mediators known to influence fibroblast activation in tissue fibrosis but not previously investigated in this regard – led to a much greater magnitude of Rα2 induction. Although both PGE 2 (via protein kinase A) and FGF-2 (via protein kinase B, also known as AKT) depended on activation of cAMP-responsive element-binding protein (CREB) for induction of Rα2 expression, they nevertheless demonstrated synergy in doing so, likely attributable to their differential utilization of distinct transcriptional start sites on the Rα2 promoter. Our data identify CREB activation via PGE 2 and FGF-2 as a previously unrecognized molecular controller of Rα2 gene induction and provide potential new insights into strategies for therapeutic manipulation of this endogenous brake on IL-13 signaling.