title: Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid.
abstract: The PPAR gamma 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 gamma or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis. The synthetic PPAR gamma agonist, GW7845, and the natural agonist 15d-PGJ2, 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 gamma 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 gamma and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the PPAR gamma antagonist, GW9662, suggests that PPAR gamma plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that PPAR gamma and RXR agonists have complex effects on monocyte metalloproteinase expression, which may have implications for therapeutic strategies.
authors.affiliation: School of Biological Sciences, University of East Anglia, and Bertram Diabetes Research Unit, Norfolk & Norwich University Hospital NHS Trust, Norwich, United Kingdom.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Worley
authors.forename: Mark D
authors.initials: MD
authors.lastname: Baugh
authors.forename: David A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
authors.forename: Aileen
authors.initials: A
authors.lastname: Hogan
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Sampson
authors.forename: Jelena
authors.initials: J
authors.lastname: Gavrilovic
mesh_terms: D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000077556:Alitretinoin; D002460:Cell Line; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000187:drug effects; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000187:drug effects; D045726:Metalloproteases / Q000096:biosynthesis* / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology; D011348:Procollagen N-Endopeptidase; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C477819:15-deoxyprostaglandin J2; D010080:Oxazoles; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000077556:Alitretinoin; C401311:GW 7845; D014443:Tyrosine; D014212:Tretinoin; D045726:Metalloproteases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D020780:Matrix Metalloproteinase 9; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; D013755:Tetradecanoylphorbol Acetate; D015230:Prostaglandin D2