Dataset Information

Transcriptional regulation of the IL-13R?2 gene in human lung fibroblasts.

ABSTRACT: Interleukin (IL)-13 is a type 2 cytokine with important roles in allergic diseases, asthma, and tissue fibrosis. Its receptor (R) ?1 is primarily responsible for the biological actions of this cytokine, while R?2 possesses a decoy function which can block IL-13 signaling. Although the expression of R?2 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 R?2 in lung fibroblasts. We confirmed previous reports that IL-13 elicited modest induction of R?2 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 R?2 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 R?2 expression, they nevertheless demonstrated synergy in doing so, likely attributable to their differential utilization of distinct transcriptional start sites on the R?2 promoter. Our data identify CREB activation via PGE2 and FGF-2 as a previously unrecognized molecular controller of R?2 gene induction and provide potential new insights into strategies for therapeutic manipulation of this endogenous brake on IL-13 signaling.

SUBMITTER: Penke LR

PROVIDER: S-EPMC6978327 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Penke Loka R LR Ouchi Hideyasu H Speth Jennifer M JM Lugogo Njira N Huang Yvonne J YJ Huang Steven K SK Peters-Golden Marc M

Scientific reports 20200123 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 fi ...[more]

PMID: 31974428

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Project description:AIM:To clarify the fractional activity of promoters from human alpha1(I) procollagen gene, the interaction between cis-elements and consensus DNA-binding proteins responsible for high promoter activity, and the potential application of promoter competitors as well as cytokines for antifibrogenesis. METHODS:Sequence between 2483 bp upstream of the start of transcription and 42 bp downstream of this site was investigated with serial 5'-deletion. The 5'-deleted promoters recombined with chloramphenicol acetyltransferase (CAT) as reporter gene were transiently transfected to human dermal fibroblasts. Electrophoretic mobility shift assay was performed to show the DNA-protein binding capacity of the promoter sequence. Cytokines including tumor necrosis factor alpha (TNFalpha) and interferons (INFs) were added to the culture medium of transiently transfected fibroblasts. Competitor DNA for the binding sites of Sp-1, Ap-1 and NF-1 was individually cotransfected transiently in order to block the promoter-driven CAT expression. RESULTS:Sequences of -2483 to +42 bp and -268 to +42 bp of human alpha1(I) procollagen gene had high activity as promoters. Binding sites for Ap-1 and Sp-1 were among the cis-regulatory elements recognizing consensus transcription factors responsible for basal promoter activity of sequence -268 to +42 bp. TNFalpha, IFNalpha, IFNbeta showed inhibitory effects on sequence -2 483 to +42 bp as promoter with activities 43%, 62% and 60% of control respectively. Transfection of the promoter competitors could reverse the promoter activity of -268 to +42 bp 40-60%. CONCLUSION:Sequences of -2 483 to +42 bp recombined with reporter gene provide an ideal construction for transcriptional study of alpha1(I) procollagen gene. The anti-collagen capacity of TNFalpha and IFNs is associated with their transcriptional regulation. Ap-1 and Sp-1 mediate the basal transcriptional activation of human alpha1(I) procollagen gene in dermal fibroblasts. Competitors for highly active promoters might be a novel potential candidate in fibrotic blockade.

Dataset Information

Transcriptional regulation of the IL-13R?2 gene in human lung fibroblasts.

Publications

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

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