Fli-1 controls transcription from the MCP-1 gene promoter, which may provide a novel mechanism for chemokine and cytokine activation

Richard, Mara Lennard; Nowling, Tamara K.; Brandon, Danielle; Watson, Dennis K.; Zhang, Xian K.

doi:10.1016/j.molimm.2014.07.013

Cited by 27 publications

(24 citation statements)

References 42 publications

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“…Together, these results indicate that globally reducing FLI1 levels in MRL/lpr mice decreases renal Neu1 and LacCer levels, but likely is not due to FLI1 regulation of Neu1 expression in the kidney. Intense LacCer staining is observed in the mesangial region of human lupus renal biopsies (12) and we here we demonstrate specific LacCer staining in the glomeruli of MRL/lpr mice (Fig. 1C).…”

Section: Resultssupporting

confidence: 70%

“…MRL/lpr Fli1 +/+ immune cells, including T cells, do not readily migrate to the kidney when transferred into MRL/lpr Fli1 +/− mice (10). Chemokines Ccl2 ( Mcp-1 ), Ccl3 ( Mip-1α ), Ccl4 ( Mip-1β ) and Ccl5 ( Rantes ) are significantly decreased at the message level in the kidneys of MRL/lpr Fli1 +/− compared to Fli1 +/+ mice and FLI1 was demonstrated to regulate the promoter activity of several different cytokine genes in endothelial cells (8, 9, 12, 13). Here we demonstrated that the expression Cxcl9 and Cxcl10 , CXCR3 ligands, also are significantly decreased in the kidneys of MRL/lpr Fli1 +/− compared to the Fli1 +/+ mice.…”

Section: Discussionmentioning

confidence: 99%

“…6E sequence) and/or non-canonical ETS binding site that remains to be identified. The putative ETS sites in hCXCR3 tested for FLI1 binding were chosen based on numerous studies, including some from our laboratory, demonstrating that FLI1 binds and acts through conserved canonical ETS sites that are more proximal to the transcription start site (9, 12, 17, 34–41). However, we recently demonstrated that FLI1 also can regulate promoters through more distal sites (12, 13).…”

Section: Discussionmentioning

confidence: 99%

“…The pGL3 mNeu1 −435 or control (pGL3 Basic) constructs (1 μg) were transfected into the MS1 cells with increasing amounts of the pcDNA3 flag-tagged FLI1 (Flag FLI1) expression vector (17) using Fugene (Promega, Madison, WI). Jurkat cell transfections were performed as previously described (18) using 0.5 μg pSG hCXCR3 and increasing amounts of FLI1 expression vectors pSG5 FLI1 or pSG5 FLI1DBM (FLI1 DNA binding mutant) (12) or pcDNA3 Flag FLI1, as indicated in the figures. Cells were stimulated with 10 ng/ml PMA and 100 ng/ml ionomycin (PMA/ion) 4 hours after transfection and cells were harvested 24 hours after transfection.…”

Section: Methodsmentioning

confidence: 99%

“…NZM2410 mice with reduced FLI1 levels ( Fli1 +/− ) were shown to have decreased numbers of renal infiltrating inflammatory cells (11). Recent studies demonstrated that FLI1 regulates the expression of MCP-1, RANTES and IL-6 (9, 12, 13). Together, these studies suggest that globally reducing FLI1 levels in lupus mouse strains improves disease by decreasing renal chemokine production and thus, inflammatory infiltration.…”

Section: Introductionmentioning

confidence: 99%

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FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain

Sundararaj

Thiyagarajan

Molano

et al. 2015

The Journal of Immunology

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The ETS factor FLI1 is a key modulator of lupus disease expression. Over-expressing FLI1 in healthy mice, results in the development of an autoimmune kidney disease similar to that observed in lupus. Lowering the global levels of FLI1 in two lupus strains (Fli1+/−) significantly improved kidney disease and prolonged survival. T cells from MRL/lpr Fli1+/− lupus mice have reduced activation and IL-4 production, Neuraminidase1 (Neu1) expression, and the levels of the glycosphingolipid (GSL) lactosylceramide (LacCer). Here we demonstrate that MRL/lpr Fli1+/− mice have significantly decreased renal Neu1 and LacCer levels. This corresponds with a significant decrease in the number of total CD3+ cells, as well as CD4+ and CD44+CD62L− T cell subsets in the kidney of MRL/lpr Fli1+/− mice compared to the Fli1+/+ nephritic mice. We further demonstrate that the percentage of CXCR3+ T cells and Cxcr3 message levels in T cells are significantly decreased and corresponds with a decrease in renal CXCR3+ cells and in Cxcl9 and Cxcl10 expression in the MRL/lpr Fli1+/− compared to the Fli1+/+ nephritic mice. Our results suggest that reducing the levels of FLI1 in MRL/lpr mice may be protective against development of nephritis in part through down-regulation of CXCR3, reducing renal T cell infiltration and GSL levels.

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Section: Resultssupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain

Sundararaj

Thiyagarajan

Molano

et al. 2015

The Journal of Immunology

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Camptothecin and Topotecan, Inhibitors of Transcription Factor Fli‐1 and Topoisomerase, Markedly Ameliorate Lupus Nephritis in (NZB × NZW)F1 Mice and Reduce the Production of Inflammatory Mediators in Human Renal Cells

Wang

Oates

Helke

et al. 2021

Arthritis & Rheumatology

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Objective. To examine the therapeutic effects of camptothecin (CPT) and topotecan (TPT), inhibitors of transcription factor Fli-1 and topoisomerase, on lupus nephritis in (NZB × NZW)F1 (NZBWF1) mice, and to examine the effects of CPT and TPT on inflammatory mediators in human renal cells.Methods. Female NZBWF1 mice were treated with vehicle, cyclophosphamide (CYC), CPT (1 mg/kg or 2 mg/kg), or TPT (0.03 mg/kg, 0.1 mg/kg, or 0. 3 mg/kg) by intraperitoneal injection twice a week, beginning at the age of 25 weeks (n = 8-10 mice per group). Blood and urine were collected for monitoring autoantibodies and proteinuria. Mice were euthanized at 40 weeks, and renal pathology scores were assessed. Human renal endothelial and mesangial cells were treated with CPT or TPT, and cytokine expression was measured.Results. None of the NZBWF1 mice treated with 1 mg/kg or 2 mg/kg of CPT or 0.3 mg/kg of TPT had proteinuria >100 mg/dl at the age of 40 weeks. One of 8 mice treated with 0.1 mg/kg of TPT and 1 of 10 mice treated with CYC had proteinuria >300 mg/dl, whereas 90% of the mice treated with vehicle had proteinuria >300 mg/dl. Compared to vehicle control, mice treated with 1 mg/kg or 2 mg/kg of CPT, 0.1 mg/kg or 0.3 mg/kg of TPT, or CYC had significantly prolonged survival, attenuated renal injury, diminished splenomegaly, reduced anti-double-stranded DNA autoantibody levels, and reduced IgG and C3 deposits in the glomeruli (all P < 0.05). Human renal cells treated with CPT or TPT had reduced expression of Fli-1 and decreased monocyte chemotactic protein 1 production following stimulation with interferon-α (IFNα) or IFNγ. Conclusion.Our findings indicate that low-dose CPT and TPT could be repurposed to treat lupus nephritis.

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Acetylation impacts Fli‐1‐driven regulation of granulocyte colony stimulating factor

et al. 2016

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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.

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Fli-1 controls transcription from the MCP-1 gene promoter, which may provide a novel mechanism for chemokine and cytokine activation

Cited by 27 publications

References 42 publications

FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain

FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain

Camptothecin and Topotecan, Inhibitors of Transcription Factor Fli‐1 and Topoisomerase, Markedly Ameliorate Lupus Nephritis in (NZB × NZW)F1 Mice and Reduce the Production of Inflammatory Mediators in Human Renal Cells

Acetylation impacts Fli‐1‐driven regulation of granulocyte colony stimulating factor

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