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Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*

The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased renal Cxcl10 mRNA levels and renal infiltrating CXCR3+ T cells that parallels reduced renal inflammatory...

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Autores principales: Wang, Xuan, Richard, Mara Lennard, Caldwell, Tomika S., Sundararaj, Kamala, Sato, Shuzo, Nowling, Tamara K., Zhang, Xian K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543418/
https://www.ncbi.nlm.nih.gov/pubmed/37790939
http://dx.doi.org/10.3389/fimmu.2023.1219279
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author Wang, Xuan
Richard, Mara Lennard
Caldwell, Tomika S.
Sundararaj, Kamala
Sato, Shuzo
Nowling, Tamara K.
Zhang, Xian K.
author_facet Wang, Xuan
Richard, Mara Lennard
Caldwell, Tomika S.
Sundararaj, Kamala
Sato, Shuzo
Nowling, Tamara K.
Zhang, Xian K.
author_sort Wang, Xuan
collection PubMed
description The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased renal Cxcl10 mRNA levels and renal infiltrating CXCR3+ T cells that parallels reduced renal inflammatory cell infiltration and renal damage. Inflammatory chemokine CXCL10 is critical for attracting inflammatory cells expressing the chemokine receptor CXCR3. The CXCL10/CXCR3 axis plays a role in the pathogenesis of various inflammatory diseases including lupus. Our data here demonstrate that renal CXCL10 protein levels are significantly lower in Fli-1 heterozygous MRL/lpr mice compared to wild-type MRL/lpr mice. Knockdown of Fli-1 significantly reduced CXCL10 secretion in mouse and human endothelial cells, and human mesangial cells, upon LPS or TNFα stimulation. The Fli-1 inhibitor, Camptothecin, significantly reduced CXCL10 production in human monocyte cells upon interferon stimulation. Four putative Ets binding sites in the Cxcl10 promoter showed significant enrichment for FLI-1; however, FLI-1 did not directly drive transcription from the human or mouse promoters, suggesting FLI-1 may regulate CXCL10 expression indirectly. Our results also suggest that the DNA binding domain of FLI-1 is necessary for regulation of human hCXCR3 promotor activity in human T cells and interactions with co-activators. Together, these results support a role for FLI-1 in modulating the CXCL10-CXCR3 axis by directly or indirectly regulating the expression of both genes to impact lupus disease development. Signaling pathways or drugs that reduce FLI-1 expression may offer novel approaches to lupus treatment.
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spelling pubmed-105434182023-10-03 Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis* Wang, Xuan Richard, Mara Lennard Caldwell, Tomika S. Sundararaj, Kamala Sato, Shuzo Nowling, Tamara K. Zhang, Xian K. Front Immunol Immunology The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased renal Cxcl10 mRNA levels and renal infiltrating CXCR3+ T cells that parallels reduced renal inflammatory cell infiltration and renal damage. Inflammatory chemokine CXCL10 is critical for attracting inflammatory cells expressing the chemokine receptor CXCR3. The CXCL10/CXCR3 axis plays a role in the pathogenesis of various inflammatory diseases including lupus. Our data here demonstrate that renal CXCL10 protein levels are significantly lower in Fli-1 heterozygous MRL/lpr mice compared to wild-type MRL/lpr mice. Knockdown of Fli-1 significantly reduced CXCL10 secretion in mouse and human endothelial cells, and human mesangial cells, upon LPS or TNFα stimulation. The Fli-1 inhibitor, Camptothecin, significantly reduced CXCL10 production in human monocyte cells upon interferon stimulation. Four putative Ets binding sites in the Cxcl10 promoter showed significant enrichment for FLI-1; however, FLI-1 did not directly drive transcription from the human or mouse promoters, suggesting FLI-1 may regulate CXCL10 expression indirectly. Our results also suggest that the DNA binding domain of FLI-1 is necessary for regulation of human hCXCR3 promotor activity in human T cells and interactions with co-activators. Together, these results support a role for FLI-1 in modulating the CXCL10-CXCR3 axis by directly or indirectly regulating the expression of both genes to impact lupus disease development. Signaling pathways or drugs that reduce FLI-1 expression may offer novel approaches to lupus treatment. Frontiers Media S.A. 2023-09-15 /pmc/articles/PMC10543418/ /pubmed/37790939 http://dx.doi.org/10.3389/fimmu.2023.1219279 Text en Copyright © 2023 Wang, Richard, Caldwell, Sundararaj, Sato, Nowling and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Wang, Xuan
Richard, Mara Lennard
Caldwell, Tomika S.
Sundararaj, Kamala
Sato, Shuzo
Nowling, Tamara K.
Zhang, Xian K.
Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*
title Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*
title_full Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*
title_fullStr Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*
title_full_unstemmed Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*
title_short Role of the transcription factor Fli-1 on the CXCL10/CXCR3 Axis*
title_sort role of the transcription factor fli-1 on the cxcl10/cxcr3 axis*
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543418/
https://www.ncbi.nlm.nih.gov/pubmed/37790939
http://dx.doi.org/10.3389/fimmu.2023.1219279
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