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The transcription factor Fli-1, amember 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 TNF 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. [ABSTRACT FROM AUTHOR]

The development of nephritis is a leading cause of morbidity and mortality in lupus patients. Although the general pathophysiological progression of lupus nephritis is known, the molecular mediators and mechanisms are incompletely understood. Previously, we demonstrated that the glycosphingolipid (GSL) catabolic pathway is elevated in the kidneys of MRL/lpr lupus mice and human lupus patients with nephritis. Specifically, the activity of neuraminidase (NEU) and expression of Neu1, an enzyme in the GSL catabolic pathway is significantly increased. To better understand the role and mechanisms by which this pathway contributes to the progression of LN, we analyzed the expression and effects of NEU activity on the function of MRL/lpr lupus-prone mesangial cells (MCs). We demonstrate that NEU1 and NEU3 promote IL-6 production in MES13 MCs. Neu1 expression, NEU activity, and IL-6 production are significantly increased in stimulated primary MRL/lpr lupus-prone MCs, and blocking NEU activity inhibits IL-6 production. NEU1 and NEU3 expression overlaps IgG deposits in MCs in vitro and in renal sections from nephritic MRL/lpr mice. Together, our results suggest that NEU activity mediates IL-6 production in lupusprone MCs possibly through an IgG-receptor complex signaling pathway. [ABSTRACT FROM AUTHOR]

The friend leukemia insertion site 1 (Fli-1) transcription factor, an Ets family member, is implicated in the pathogenesis of systemic lupus erythematosus in human patients and murine models of lupus. Lupus-prone mice with reduced Fli-1 expression have significantly less nephritis, prolonged survival, and decreased infiltrating inflammatory cells into the kidney. Inflammatory chemokines, including CCL5, are critical for attracting inflammatory cells. In this study, decreased CCL5 mRNA expression was observed in kidneys of lupus-prone NZM2410 mice with reduced Fli-1 expression. CCL5 protein expression was significantly decreased in endothelial cells transfected with Fli-1-specific small interfering RNA compared with controls. Fli-1 binds to endogenous Ets binding sites in the distal region of the CCL5 promoter. Transient transfection assays demonstrate that Fli-1 drives transcription from the CCL5 promoter in a dose-dependent manner. Both Ets1, another Ets family member, and Fli-1 drive transcription from the CCL5 promoter, although Fli-1 transactivation was significantly stronger. Ets1 acts as a dominant-negative transcription factor for Fli-1, indicating that they may have at least one DNA binding site in common. Systematic deletion of DNA binding sites demonstrates the importance of the sites located within a 225-bp region of the promoter. Mutation of the Fli-1 DNA binding domain significantly reduces transactivation of the CCL5 promoter by Fli-1. We identified a novel regulator of transcription for CCL5. These results suggest that Fli-1 is a novel and critical regulator of proinflammatory chemokines and affects the pathogenesis of disease through the regulation of factors that recruit inflammatory cells to sites of inflammation. [ABSTRACT FROM AUTHOR]

Purpose of Review: Mesangial cells are critical for the proper function of the glomerulus, playing roles in structural support and injury repair. However, they are also early responders to glomerular immune complex deposition and contribute to inflammation and fibrosis in lupus nephritis. This review highlights recent studies identifying signaling pathways and mediators in mesangial cell response to lupus-relevant stimuli., Recent Findings: Anti-dsDNA antibodies, serum, or plasma from individuals with lupus nephritis, or specific pathologic factors activated multiple signaling pathways. These pathways largely included JAK/STAT/SOCS, PI3K/AKT, and MAPK and led to induction of proliferation and expression of multiple proinflammatory cytokines, growth factors, and profibrotic factors. NFκB activation was a common mediator of response. Mesangial cells proliferate and express a wide array of proinflammatory/profibrotic factors in response to a variety of lupus-relevant pathologic stimuli. While some of the responses are similar, the mechanisms involved appear to be diverse depending on the stimulus. Future studies are needed to fully elucidate these mechanisms with respect to the diverse milieu of stimuli., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fucoidan, a sulfated polysaccharide, has significant cytotoxic activity against tumor cells; however, the mechanism(s) of this action remains poorly understood. The present study was designed to determine the in vitro and in vivo effects of fucoidan and their molecular mechanisms. Fucoidan from Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan, delayed tumor growth in Sarcoma 180 (S-180)-bearing mice. However, it failed to inhibit S-180 cell growth in vitro. Activated macrophages are known to have anti-tumor effects. Murine RAW264.7 macrophages stimulated with fucoidan exerted cytotoxicity towards S-180 cells in vitro. This cytotoxicity was associated with nitric oxide (NO) production. Both cytocidal effect and NO production were significantly inhibited by L-NAME, an inhibitor of NO synthase (NOS). Furthermore, activation of nuclear factor-κB was a key step in the transcriptional activation of the inducible NOS gene. Taken together, our results indicate that the anti-tumor activity of fucoidan on S-180 cells is mediated through increased NO production by fucoidan-stimulated macrophages via nuclear factor-κB-dependent signaling pathway.