Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney

Suzuki, Eiji; Karam, Eva; Williams, Sarah; Watson, Dennis K.; Gilkeson, Gary S.; Zhang, Xian K.

doi:10.1016/j.clim.2012.09.006

Cited by 34 publications

(77 citation statements)

References 45 publications

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“…MRL/ lpr mice deficient in MCP-1 showed a reduction in macrophage and T cell recruitment to the kidney and glomerulus as well as reduced proteinuria, a decrease in apoptotic cells, and prolonged survival (32). Similar results have also been observed in Fli-1 +/− NZM2410 mice, which exhibit significantly less infiltration of inflammatory cells and decreased expression of MCP-1 in kidneys (33). Based on our previous results showing decreased expression of MCP-1 in kidneys and primary endothelial cells, and demonstrating that Fli-1 binds to the MCP-1 promoter (33); it appears that there is a direct link between Fli-1 and MCP-1 gene expression.…”

Section: Introductionsupporting

confidence: 81%

“…Fli-1 and NFκB family member, p65, were found to interact to activate transcription from the MCP-1 promoter, while Sp1 and p50 inhibit this interaction. While Fli-1 is able to bind at least three cis-regulatory regions in the promoter (33), it appears that similar to previous studies (10, 11, 13) binding sites in the distal and proximal regions are of greatest importance for transcriptional activation. Combined with our previous results, we have demonstrated that Fli-1 plays a critical role in the activation of the proinflammatory chemokine MCP-1.…”

Section: Introductionsupporting

confidence: 65%

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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

Richard

Nowling

Brandon

et al. 2015

Molecular Immunology

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Regulation of proinflammatory cytokines and chemokines is a primary role of the innate immune response. MCP-1 is a chemokine that recruits immune cells to sites of inflammation. Expression of MCP-1 is reduced in primary kidney endothelial cells from mice with a heterozygous knockout of the Fli-1 transcription factor. Fli-1 is a member of the Ets family of transcription factors, which are evolutionarily conserved across several organisms including Drosophilla, Xenopus, mouse and human. Ets family members bind DNA through a consensus sequence GGAA/T, or Ets binding site (EBS). Fli-1 binds to EBSs within the endogenous MCP-1 promoter by ChIP assay. In this study, transient transfection assays indicate that the Fli-1 gene actively promotes transcription from the MCP-1 gene promoter in a dose-dependent manner. Mutation of the DNA binding domain of Fli-1 demonstrated that Fli-1 activates transcription of MCP-1 both directly, by binding to the promoter, and indirectly, likely through interactions with other transcription factors. Another Ets transcription factor, Ets-1, was also tested, but failed to promote transcription. While Ets-1 failed to drive transcription independently, a weak synergistic activation of the MCP-1 promoter was observed between Ets-1 and Fli-1. In addition, Fli-1 and the NFκB family member p65 were found to interact synergistically to activate transcription from the MCP-1 promoter, while Sp1 and p50 inhibit this interaction. Deletion studies identified that EBSs in the distal and proximal MCP-1 promoter are critical for Fli-1 activation from the MCP-1 promoter. Together, these results demonstrate that Fli-1 is a novel regulator of the proinflammatory chemokine MCP-1, that interacts with other transcription factors to form a complex transcriptional mechanism for the activation of MCP-1 and mediation of the inflammatory response.

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Section: Introductionsupporting

confidence: 81%

Section: Introductionsupporting

confidence: 65%

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

Richard

Nowling

Brandon

et al. 2015

Molecular Immunology

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“…Overexpression of Fli-1 in transgenically altered non-autoimmune mice and Fli-1 knockout mice both result in a lupus-like phenotype including renal disease. [36][37][38] Reducing Fli-1 expression improves disease and survival in the murine models 39 40 and in human SLE a specific microsatellite length of the Fli-1 promotor has been reported to be significantly more prevalent in patients with SLE without nephritis. 41 In our cohort, Fli-1 was preferentially expressed in subjects with active renal disease.…”

Section: Discussionmentioning

confidence: 99%

Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection

et al. 2016

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“…Fli-1 specific siRNA was transfected into the MS1 endothelial cell line and expression of the Fli-1 protein was reduced around 90% as reported previously (31). As shown in Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Additionally it has been observed that peripheral blood lymphocytes (PBLs) from SLE patients have significantly increased expression of Fli-1, which has been linked to activity of the disease (22). We recently discovered that expression of the inflammatory chemokine Chemokine (C-C motif) ligand 2 (CCL2, also known as monocyte chemotactic protein-1, MCP-1) in endothelial cells is directly regulated by Fli-1 (31). In this study we investigated whether Fli-1 affects lupus disease development by regulating the expression of IL-6 in a murine model of lupus.…”

Section: Introductionmentioning

confidence: 99%

A Critical Role of the Transcription Factor Fli‐1 in Murine Lupus Development by Regulation of Interleukin‐6 Expression

Sato

Richard

Brandon

et al. 2014

Arthritis & Rheumatology

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Objective The Fli-1 transcription factor is implicated in the pathogenesis of systemic lupus erythematosus (SLE) in both human patients and animal models. Dysregulation of interleukin 6 (IL-6) is also associated with SLE. We investigated whether Fli-1 directly regulates the expression of IL-6. Methods Sera were collected from wild-type and Fli-1 heterozygous (Fli-1+/−) MRL/lpr mice and the concentration of IL-6 was measured by ELISA. Expression of IL-6 in the kidney was measured by real-time PCR. T cells were isolated from wild-type and Fli-1+/− MRL/lpr mice and stimulated with CD3/CD28 beads, and the concentration of IL-6 in the supernatants was measured by ELISA. MS1 endothelial cells were transfected with Fli-1 and control siRNA, and the production of IL-6 was compared after lipopolysaccharides (LPS) stimulation. A chromatin immunoprecipitation (ChIP) assay was performed to determine whether Fli-1binds to the IL-6 promoter region. Transient transfections with the NIH 3T3 cell line were performed to study if Fli-1 regulates the expression of IL-6. Results Fli-1+/− MRL/lpr mice had significantly decreased IL-6 in sera and reduced expression of IL-6 in kidneys compared to wild-type littermates. The T cells isolated from Fli-1+/− MRL/lpr mice produced less IL-6. Inhibiting the expression of Fli-1 in endothelial cells resulted in reduced production of IL-6. The ChIP assay revealed direct binding of Fli-1 to three regions within the IL-6 promoter. Fli-1 activated transcription from the IL-6 promoter in a dose-dependent manner. Conclusion Fli-1 directly regulates IL-6 expression as one of possible mechanisms for the protective effect in lupus of decreased Fli-1 expression.

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Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney

Cited by 34 publications

References 45 publications

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

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

Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection

A Critical Role of the Transcription Factor Fli‐1 in Murine Lupus Development by Regulation of Interleukin‐6 Expression

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