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Eur J Immunol. 2016 Oct;46(10):2322-2332. doi: 10.1002/eji.201646315. Epub 2016 Aug 16.

Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor.

Author information

1
Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
2
Jinan Central Hospital, Shandong University, Jinan, Shangdong, China.
3
Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
4
Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, USA. zhangjo@musc.edu.
5
Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA. zhangjo@musc.edu.

Abstract

Fli-1 has emerged as a critical regulator of inflammatory mediators, including MCP-1, CCL5, and IL-6. The cytokine, granulocyte colony stimulating factor (G-CSF) regulates neutrophil precursor maturation and survival, and activates mature neutrophils. Previously, a significant decrease in neutrophil infiltration into the kidneys of Fli-1+/- lupus-prone mice was observed. In this study, a significant decrease in G-CSF protein expression was detected in stimulated murine and human endothelial cells when expression of Fli-1 was inhibited. The murine G-CSF promoter contains numerous putative Fli-1 binding sites and several regions within the proximal promoter are significantly enriched for Fli-1 binding. Transient transfection assays indicate that Fli-1 drives transcription from the G-CSF promoter and mutation of the Fli-1 DNA binding domain resulted in a 94% loss of transcriptional activation. Mutation of a known acetylation site, led to a significant increase in G-CSF promoter activation. The histone acetyltransferases p300/CBP and p300/CBP associated factor (PCAF) significantly decrease Fli-1 specific activation of the G-CSF promoter. Thus, acetylation appears to be an important mechanism behind Fli-1 driven activation of the G-CSF promoter. These results further support the theory that Fli-1 plays a major role in the regulation of several inflammatory mediators, ultimately affecting inflammatory disease pathogenesis.

KEYWORDS:

Cytokines; Fli-1; G-CSF; Gene regulation; Inflammation; Transcriptional factors

PMID:
27431361
PMCID:
PMC5175580
DOI:
10.1002/eji.201646315
[Indexed for MEDLINE]
Free PMC Article

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