Liver X receptor agonists inhibit tissue factor expression in macrophages

Abstract

Exposure of blood to tissue factor (TF) rapidly initiates the coagulation serine protease cascades. TF is expressed by macrophages and other types of cell within atherosclerotic lesions and plays an important role in thrombus formation after plaque rupture. Macrophage TF expression is induced by pro‐inflammatory stimuli including lipopolysaccharide (LPS), interleukin‐1β and tumor necrosis factor‐α. Here we demonstrate that activation of liver X receptors (LXRs) LXRα and LXRβ suppresses TF expression. Treatment of mouse peritoneal macrophages with synthetic LXR agonist T0901317 or GW3965 reduced TF expression induced by pro‐inflammatory stimuli. LXR agonists also suppressed TF expression and its activity in human monocytes. Human and mouse TF promoters contain binding sites for the transcription factors AP‐1, NFκB, Egr‐1 and Sp1, but no LXR‐binding sites could be found. Cotransfection assays with LXR and TF promoter constructs in RAW 264.7 cells revealed that LXR agonists suppressed LPS‐induced TF promoter activity. Analysis of TF promoter also showed that inhibition of TF promoter activity by LXR was at least in part through inhibition of the NFκB signaling pathway. In addition, in vivo, LXR agonists reduced TF expression within aortic lesions in an atherosclerosis mouse model as well as in kidney and lung in mice stimulated with LPS. These findings indicate that activation of LXR results in reduction of TF expression, which may influence atherothrombosis in patients with vascular disease.

Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

“…Our results with LPS-treated cells support these observations, but the fact that the inflammatory response to IFN-g remains almost unchanged after cholesterol loading is intriguing and may help explain why a considerable percentage of foam cells within established atherosclerotic lesions still display a classically activated phenotype (49). Remarkably, the high-affinity synthetic agonist GW3965 was able to repress IFN-gdependent responses in acLDL-induced foam cells, which is in agreement with previous reports demonstrating anti-inflammatory actions of synthetic LXR agonists within the artery wall in vivo (12,50).…”

The synthetic liver X receptor agonist GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro

“…We found that the production of LXRs was upregulated by LPS stimulation (Fig. 1a, b), suggesting that activation of LXRs during stress constitutes an endogenous protective mechanism in human islets, as has been found to be the case in macrophages [13] and human monocytes [12]. Adding GW3965 to LPS-stimulated human islets further upregulated the levels of LXRs (Fig.…”

“…In addition, in vivo and in vitro studies have demonstrated that activation of LXR agonists antagonises inflammatory gene expression in mouse macrophages [10], microglia and astrocytes [11], and human monocytes [12]. In cultured murine and human macrophages the synthetic LXR agonist GW3965 has been shown to reduce cytokine-induced tissue factor (TF) production [13] and we have previously shown that GW3965 dose-dependently attenuated LPS-induced release of TNF-α and prostaglandin E 2 by hepatic Kupffer cells in vitro as well as in vivo [14]. Human islets exposed to human blood trigger an instant blood-mediated inflammatory reaction, characterised by platelet consumption and activation of the coagulation and complement systems, and this activation may impair engraftment after intraportal islet transplantation [15].…”

Liver X receptors as integrators of metabolic and inflammatory signaling

“…LXR ligands repress these genes in macrophages derived from WT, Lxra -/-, and Lxrb -/-mice but are unable to do so in macrophages from Lxrab -/-mice, indicating that both LXR isoforms possess antiinflammatory activity. Subsequent work has suggested that tissue factor and osteopontin, both inflammatory genes associated with an increased risk for developing atherosclerosis, are subject to similar repression by LXR ligands in macrophages (75,76).…”