Liver X Receptor-dependent Repression of Matrix Metalloproteinase-9 Expression in Macrophages

Abstract

Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix (ECM) components during normal and pathogenic tissue remodeling. Inappropriate expression of these enzymes contributes to the development of vascular pathology, including atherosclerosis. MMP-9 is expressed in its active form in atherosclerotic lesions and is believed to play an important role in vascular remodeling, smooth muscle cell migration, and plaque instability. We demonstrate here that the liver X receptors (LXRs) LXR␣ and LXR␤ inhibit basal and cytokine-inducible expression of MMP-9. Treatment of murine peritoneal macrophages with the synthetic LXR agonists GW3965 or T1317 reduces MMP-9 mRNA expression and blunts its induction by pro-inflammatory stimuli including lipopolysaccharide, interleukin-1␤, and tumor necrosis factor ␣. In contrast, macrophage expression of MMP-12 and MMP-13 is not altered by LXR ligands. We further show that the ability of LXR ligands to regulate MMP-9 expression is strictly receptor-dependent and is not observed in macrophages obtained from LXR␣␤ null mice. Analysis of the 5-flanking region of the MMP-9 gene indicates that LXR/RXR heterodimers do not bind directly to the MMP-9 promoter. Rather, activation of LXRs represses MMP-9 expression, at least in part through antagonism of the NFB signaling pathway. These observations identify the regulation of macrophage MMP-9 expression as a mechanism whereby activation of LXRs may impact macrophage inflammatory responses. Matrix metalloproteinases (MMPs)1 are a large family of Zn 2ϩ -containing endopeptidases that play a key role in degrading extracellular matrix (ECM) components. MMP activation has been implicated in physiological and pathological tissue remodeling in multiple contexts, including cancer invasion, inflammation, organ development, angiogenesis, and wound healing (1). The MMP family contains more than 20 members, including collagenases, gelatinases, matrilysins, stromelysins, and metalloelastases. Active MMPs trigger the degradation of ECM components such as collagens, elastin, gelatin, fibronectin, laminin, and proteoglycans. In addition, MMP activity induces the processing of several non-ECM proteins, including ␣ 1 -antitrypsin, ␣ 2 -macroglobulin, plasminogen, and serum amyloid protein A (2). The MMP activity is regulated at several levels, including gene transcription, cellular secretion, activation of proenzymes, and binding to tissue inhibitors of metalloproteinases (TIMPs). Increasing experimental evidence supports a direct link between elevated MMP activity and diseases that involve enhanced turnover of the ECM, such as atherosclerosis and rheumatoid arthritis (3).Enhanced expression of several MMPs, including MMP-9 and MMP-1, has been documented in both murine and human atherosclerotic lesions. Macrophages are a primary source of MMP expression, and their elaboration of these enzymes is believed to contribute to smooth muscle cell migration, neointima formation, and plaque rupture (4). MMP-9 degrades vessel wall collagen...

Fucosyltransferase IV Enhances Expression of MMP-12 Stimulated by EGF via the ERK1/2, p38 and NF-kB Pathways in A431Cells

“…The expression and secretion of ECM-modifying MMPs is an important determinant of tumor invasion. MMP expression is regulated at the transcriptional level and the MMP promoters contain NF-kB (Chen et al, 2009;Oh et al, 2009), which have been shown to regulate MMP-12 promoter activity (Castrillo et al, 2003;Sampath et al, 2006).…”

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

“…Moreover, the increase in PTPN1 production and activity induced by TNFα was completely prevented by T0901317. The mechanisms of this inhibitory action are unknown, and so far no NR1HR response elements have being identified on the Ptpn1 promoter, although the induction by cytokines of the expression of other genes, such as that encoding matrix metalloproteinase-9 in macrophages, was repressed by NR1HR activation [44]. One group has identified on the Ptpn1 promoter two regulatory elements that recognise Y box-binding protein-1 and Sp family transcription factors, both of which are required for optimal promoter activity [45].…”

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

“…32,48,49 In animal models of atherosclerosis, such as apolipoprotein E-deficient (apoE Ϫ/Ϫ ) and LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice, we found that LXR ligand treatment reduced the development of atherosclerosis. 34 Moreover, recent studies revealed that the LXR signaling pathway links innate immunity to macrophage cholesterol metabolism.…”

“…30 In addition LXRs also play a role in innate immunity and regulate inflammatory gene expression in macrophages. [31][32][33] Indeed, synthetic LXR agonists have been shown to both delay the development of atherosclerosis in genetically prone mouse models and induce regression of preexisting atherosclerotic lesions. 34 -36 In the absence of ligand, heterodimers of LXR and retinoid X receptor, in complex with corepressors such as nuclear receptor corepressor (NCoR) and the related factor SMRT (Silencing Mediator of Retinoic acid and Thyroid hormone receptors), are bound to LXR-responsive elements and inhibit target gene transcription.…”