Faculty Collaboration Database

Expression of GM-CSF Is Regulated by Fli-1 Transcription Factor, a Potential Drug Target. J Immunol 2021 Jan 01;206(1):59-66

Date

12/04/2020

Pubmed ID

33268481

Pubmed Central ID

PMC7942804

DOI

10.4049/jimmunol.2000664

Scopus ID

2-s2.0-85098732896 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

Friend leukemia virus integration 1 (Fli-1) is an ETS transcription factor and a critical regulator of inflammatory mediators, including MCP-1, CCL5, IL-6, G-CSF, CXCL2, and caspase-1. GM-CSF is a regulator of granulocyte and macrophage lineage differentiation and a key player in the pathogenesis of inflammatory/autoimmune diseases. In this study, we demonstrated that Fli-1 regulates the expression of GM-CSF in both T cells and endothelial cells. The expression of GM-CSF was significantly reduced in T cells and endothelial cells when Fli-1 was reduced. We found that Fli-1 binds directly to the GM-CSF promoter using chromatin immunoprecipitation assay. Transient transfection assays indicated that Fli-1 drives transcription from the GM-CSF promoter in a dose-dependent manner, and mutation of the Fli-1 DNA binding domain resulted in a significant loss of transcriptional activation. Mutation of a known phosphorylation site within the Fli-1 protein led to a significant increase in GM-CSF promoter activation. Thus, direct binding to the promoter and phosphorylation are two important mechanisms behind Fli-1-driven activation of the GM-CSF promoter. In addition, Fli-1 regulates GM-CSF expression in an additive manner with another transcription factor Sp1. Finally, we demonstrated that a low dose of a chemotherapeutic drug, camptothecin, inhibited expression of Fli-1 and reduced GM-CSF production in human T cells. These results demonstrate novel mechanisms for regulating the expression of GM-CSF and suggest that Fli-1 is a critical druggable regulator of inflammation and immunity.

Author List

Wang X, Lennard Richard M, Li P, Henry B, Schutt S, Yu XZ, Fan H, Zhang W, Gilkeson G, Zhang XK

Author

Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Camptothecin
Endothelium
Gene Expression Regulation
Granulocyte-Macrophage Colony-Stimulating Factor
Humans
Jurkat Cells
Mice
Molecular Targeted Therapy
NIH 3T3 Cells
Promoter Regions, Genetic
Proto-Oncogene Protein c-fli-1
RNA, Small Interfering
Sp1 Transcription Factor
T-Lymphocytes
Topoisomerase I Inhibitors