Metalloproteinase Expression in PMA-stimulated THP-1 Cells

Abstract

The PPAR␥ agonists, thiazolidinediones (TZDs), have anti-inflammatory properties as well as increasing insulin sensitivity. This has widened their therapeutic scope to treat inflammatory diseases such as atherosclerosis in addition to Type 2 Diabetes. TZDs are known to reduce monocyte/macrophage expression of Matrix metalloproteinase (MMP)-9, which is implicated in atherosclerotic plaque destabilization. This study aims to identify other metalloproteinase genes of the ADAM (A Disintegin And Metalloproteinase) and ADAMTS families that are regulated by PPAR␥ or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis. The synthetic PPAR␥ agonist, GW7845, and the natural agonist 15d-PGJ 2 , suppressed PMA stimulated MMP-9 in human monocyte-like cells (THP-1) only in the presence of 9-cis-retinoic acid. Quantitative Real-Time PCR showed that this reduction was regulated at the mRNA level. Expression of ADAMs 8, 9, and 17 were increased, and ADAM15 was decreased by stimulation of THP-1 with PMA, although these ADAMs were not regulated by PPAR␥ or RXR agonists. PMA-induced ADAM28 expression was further enhanced by the addition of 9-cis-retinoic acid. ADAMTS4, implicated in rheumatoid arthritis, was expressed in THP-1 cells, and significantly increased after 24 h of PMA stimulation. ADAMTS4 expression was suppressed by both PPAR␥ and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the PPAR␥ antagonist, GW9662, suggests that PPAR␥ plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that PPAR␥ and RXR agonists have complex effects on monocyte metalloproteinase expression, which may have implications for therapeutic strategies. Peroxisome proliferator-activated receptor (PPAR)1 -␥ has been identified as the target receptor of the thiazolidinediones (TZD), a group of insulin sensitizing drugs now widely used for treating Type 2 diabetes (1). PPAR␥ was originally located in human liver, heart, and skeletal muscle (2). Many of the known target genes are involved in fatty acid metabolism, as PPAR␥ is a key component in regulating adipocyte differentiation, and controlling plasma lipid and sugar levels. When ligand-activated, PPAR␥ binds the PPAR response element (PPRE) as a dimer with the retinoid X receptor (RXR) (3), and affects the transcription of PPAR␥ target genes. RXR is also able to form homodimers, and heterodimers with other nuclear receptors such as the retinoic acid receptor (RAR) and liver X receptor (LXR). The endogenous agonist of RXR is 9-cis-retinoic acid, a natural derivative of vitamin A, which is also able to activate the RAR. Natural ligands of PPAR␥ include polyunsaturated fatty acids and their metabolites, in particular the lipoxygenase products of arachidonic acid and linoleic acid, 15-hydroxyeicosatetraenoic acid and 13-hydroxyoctadecadienoic acid, respectively (4), and 15-deoxy-⌬ 12-14 -Prostaglandin J 2 (15d-PGJ 2 ) (5, 6).PPAR␥ has now been detec...

Peroxisome Proliferator-activated Receptor-γ Down-regulates Chondrocyte Matrix Metalloproteinase-1 via a Novel Composite Element

“…PPAR␥ agonists were also found to inhibit MMP3 expression in human rheumatoid fibroblast-like synoviocytes (44). Down-regulation of MMP9 by natural (15d-PGJ2) and synthetic (GW7845) PPAR-␥ ligands in PMA-stimulated THP-1 monocytes has been consistently observed (31). An inhibition of MMP13 expression by Rtz was also reported by Fahmi et al (3) in human chondrocytes.…”

Differential regulation of tumor necrosis factor-α-converting enzyme and angiotensin-converting enzyme by type I and II interferons in human normal and leukemic myeloid cells

“…Thus, the IFN-induced downregulation of surface TACE seemed to likely occur via the internalization of TACE. Previous studies showed that PMA upregulated TACE transcripts in leukemic myeloid tamm-horsefall protein-1 (THP-1) cells (Worley et al, 2003) and downregulated surface TACE (Doedens and Black, 2000). This downregulation occurred via the internalization and degradation of TACE molecules (Doedens and Black, 2000).…”

Pivotal Role of Serum- and Glucocorticoid-Inducible Kinase 1 in Vascular Inflammation and Atherogenesis

“…Monocyte as well as monocyte-derived macrophage MMP-9 is tightly regulated at the transcriptional level by the transcription factor NF-κB 2,16 and rapidly increases in processes involved in vascular inflammation and atherogenesis. 11,53 However, the precise factors that stimulate MMP elaboration in lesion-associated macrophages have not been well characterized to date. 9 NF-κB is active in lesion-prone regions and NF-κB-regulated inflammatory responses play major roles in atherosclerotic lesion initiation and progression of atherogenesis.…”

“…4 During all stages of atherogenesis, monocytes and macrophages secrete proteolytic enzymes, which may influence plaque composition or stability. 10,11 Migration of macrophages into atherosclerotic tissue as well as subsequent plaque remodeling and progression require the degradation of tissue matrix proteins by matrix metalloproteinases (MMPs) such as MMP-2 or MMP-9.…”