title: PGJ2 inhibition of LPS-induced inflammatory mediator expression from rat alveolar macrophages.
abstract: Studies suggested that 15-deoxy-delta-(12,14)-prostaglandin J2 (PGJ2) may exert anti-inflammatory effects, including in the lung. Thus, in vitro studies were conducted to (1) investigate whether PGJ2 inhibited the production of inflammatory mediators from lipopolysaccharide (LPS)-exposed primary rat alveolar macrophages (AM), and (2) investigate possible mechanisms underlying PGJ2-mediated inhibition of inflammatory mediator production. These studies determined that PGJ2 inhibited LPS-induced nitric oxide (NO) production in a concentration- and time-dependent manner. PGJ2-mediated inhibition of NO, as well as of tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 (MIP-2), was also determined to be dependent on the time of addition of PGJ2 relative to LPS, and suggested the PGJ2 inhibitory mechanism is an early event. PGJ2 was shown not to interfere with binding or internalization of LPS by AM, indicating this was not responsible for PGJ2 inhibitory effects. Another possible mechanism underlying PGJ2-mediated inhibition was via peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, biochemical studies suggested that PGJ2-mediated inhibition was not occurring through PPAR-gamma dependent mechanism, and molecular studies further established that both LPS and PGJ2 decrease PPAR-gamma mRNA expression. A third possible mechanism underlying PGJ2-mediated inhibition was by alteration of nuclear factor (NF)-kappaB. Molecular studies confirmed that LPS stimulated NF-kappaB mRNA expression, and PGJ2 reduced this stimulation, which is consistent with PGJ2 effect on LPS-induced production of NO, TNF-alpha and MIP-2. Thus, data in this study established that PGJ2 inhibited LPS-induced inflammatory mediator production in rat AM, and this inhibition is mediated, at least in part, by reducing the expression of NF-kappaB mRNA.
authors.affiliation: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA. dporter@cdc.gov
authors.forename: Dale W
authors.initials: DW
authors.lastname: Porter
authors.forename: Michael
authors.initials: M
authors.lastname: Wolfarth
authors.forename: Shih-Houng
authors.initials: SH
authors.lastname: Young
authors.forename: Murali K
authors.initials: MK
authors.lastname: Rao
authors.forename: Terence
authors.initials: T
authors.lastname: Meighan
authors.forename: Mark
authors.initials: M
authors.lastname: Barger
authors.forename: Michael E
authors.initials: ME
authors.lastname: Andrew
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Huffman
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D054426:Chemokine CXCL2; C513296:Cxcl2 protein, rat; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2