Abstract
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 E2 (PGE2) 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 PGE2 (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 PGE2 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.
Highlights
IntroductionTSS1 was shown to be the major start site for transcription initiated by PGE2, whereas TSS2 was exclusively used for transcription initiated by FGF-2
While Rα1 is well known to exert biological actions via JAK/STAT6 signaling, Rα2 in most experimental systems – including lung Fibs54–57 – acts as a decoy receptor dampening the actions of IL-13
We found that Rα2 gene transcription in human lung Fibs was strongly induced by PGE2, FGF-2, and PDGF – mediators known to exhibit diverse regulatory effects on Fibs
Summary
TSS1 was shown to be the major start site for transcription initiated by PGE2, whereas TSS2 was exclusively used for transcription initiated by FGF-2. CREB-mediated Rα2 transcription elicited by the combination of an agonist utilizing TSS2 (FGF-2) along with an agonist utilizing TSS1 (either PGE2 or IL-13) was accompanied by activation of both TSSs, likely explaining the synergistic effects observed for Rα2 expression. The activation of transcription from both TSS1 and TSS2 provides a potential explanation for synergistic patterns of induction by various combinations of stimuli. In this regard, it is of interest to note that synergistic induction of Rα2 in lung Fibs was previously observed with the combination of IL-17 and either IL-13 or TNF-α69. The possibility of functional differences between TSS1- and TSS2-initiated Rα2 transcripts will require further investigatio
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