title: 15-Deoxy-Delta(12,14)-prostaglandin J(2) and troglitazone regulation of the release of phospholipid metabolites, inflammatory cytokines and proteases from human gestational tissues.
abstract: Phospholipid-derived mediators, inflammatory cytokines and extracellular matrix remodelling enzymes are all involved in the initiation of human labour and delivery. We have previously demonstrated that natural and synthetic PPAR-gamma ligands regulate LPS-stimulated pro-inflammatory cytokine release from human gestational tissues, however, the effect of these ligands on the basal and/or LPS-induced expression of prostaglandins and proteases is not known. Therefore, the aim of this study was to determine the effects of 15d-PGJ(2) and troglitazone on the expression of basal and LPS-stimulated inflammatory mediators in human gestational tissues. Human placenta, amnion and choriodecidua (n=5) were incubated in the presence or absence of 15 microM 15d-PGJ(2) and 30 microM troglitazone under basal and LPS-stimulated (10 microg/ml) conditions. Treatment of placenta, amnion and choriodecidua with both 15d-PGJ(2) and troglitazone decreased basal and LPS-stimulated IL-1beta, IL-6, IL-10 and TNF-alpha release. Basal type II PLA(2) release from placental tissues was also significantly decreased by 15d-PGJ(2) and troglitazone. There was no effects of 15d-PGJ(2) and troglitazone on cPLA(2) protein expression. Both 15d-PGJ(2) and troglitazone significantly decreased basal and LPS-stimulated PGE(2) and PGF(2alpha) release from placenta and amnion. However, in choriodecidua, although 15d-PGJ(2) decreased basal and/or LPS-stimulated PGE(2) and PGF(2alpha) release, there was an increase in PGE(2) and PGF(2alpha) release in the presence of troglitazone. 15d-PGJ(2) and troglitazone inhibited MMP-9 release from human amnion. NF-kappaB DNA binding activity and NF-kappaB p65 protein expression was inhibited by treatment with 15d-PGJ(2) in human amnion. There was no effect of 15d-PGJ(2) or troglitazone on PPAR-gamma protein, and GW9662 failed to alleviate 15d-PGJ(2) and troglitazone inhibition of IL-6 and TNF-alpha release in placenta, amnion and choriodecidua. The data demonstrated in this study suggest that the 15d-PGJ(2) and troglitazone exhibit anti-inflammatory properties in human gestational tissues via PPAR-gamma independent actions.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Melbourne and Mercy Perinatal Research Centre, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia. mlappas@unimelb.edu.au
authors.forename: M
authors.initials: M
authors.lastname: Lappas
authors.forename: M
authors.initials: M
authors.lastname: Permezel
authors.forename: G E
authors.initials: GE
authors.lastname: Rice
mesh_terms: D000813:Anilides / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D007378:Interleukins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology; D010741:Phospholipases A / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002839:Chromans; D016207:Cytokines; D007378:Interleukins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D010743:Phospholipids; D045162:Thiazolidinediones; D015237:Dinoprost; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D020782:Matrix Metalloproteinases; D000077288:Troglitazone; D015232:Dinoprostone; D015230:Prostaglandin D2