title: Statins potentiate the IFN-gamma-induced upregulation of group IIA phospholipase A2 in human aortic smooth muscle cells and HepG2 hepatoma cells.
abstract: The present study shows that the incubation of human aortic smooth muscle cells (HASMC) and HepG2 cells with atorvastatin and mevastatin as HMG-CoA reductase inhibitors potentiated the interferon-gamma (INF-gamma)-induced group IIA phospholipase A(2) (sPLA(2)-IIA) expression in a dose- and time-dependent manner. The effect of statins on sPLA(2)-IIA expression was reduced by mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Inversely, inhibitors of the farnesyl transferase and geranylgeranyl transferase-I mimicked the effects of statins. Clostridium difficile toxin B (TcdB), Y-27632 and H-1152, functioning as inhibitors of Rho proteins and Rho-associated kinase, also augmented the sPLA(2)-IIA expression in combination with IFN-gamma. The same effects were observed when inhibitors of mitogen-activated/extracellular response protein kinase kinase (MEK), PD98059 or U0126 were used. Further, the Janus kinase-2 (Jak2)-specific inhibitor, AG-490 and inhibitors of nuclear factor-kappaB (NFkappaB) abrogated the sPLA(2)-IIA elevating effects of statins, TcdB and PD98059 in the presence of IFN-gamma. This cytokine alone increased the NFkappaB p65 and CAAT-enhancer-binding protein-beta (C/EBP-beta) activity in HASMC nuclear extract, but only C/EBP-beta was further augmented when the cells were incubated in addition to IFN-gamma with atorvastatin, H-1152, PD98059 or U0126. Moreover, after the incubation of cells with atorvastatin and IFN-gamma the stability of sPLA-(2)IIA mRNA significantly increased in comparison to those after incubation with IFN-gamma alone. In conclusion, the obtained data suggest that (i) the expression of sPLA(2)-IIA is negatively regulated by RhoA/Rho-associated kinase and MEK/ERK signaling pathways and (ii) statins, because of their ability to down-regulate these pathways, can potentiate the IFN-gamma-induced sPLA(2)-II expression at transcriptional and post-transcriptional levels.
authors.affiliation: Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Institut für Klinische Chemie und Laboratoriumsmedizin, Germany. menschik@rcs.urz.tu-dresden.de
authors.forename: Mario
authors.initials: M
authors.lastname: Menschikowski
authors.forename: Albert
authors.initials: A
authors.lastname: Hagelgans
authors.forename: Ben
authors.initials: B
authors.lastname: Heyne
authors.forename: Ute
authors.initials: U
authors.lastname: Hempel
authors.forename: Volker
authors.initials: V
authors.lastname: Neumeister
authors.forename: Peter
authors.initials: P
authors.lastname: Goez
authors.forename: Werner
authors.initials: W
authors.lastname: Jaross
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siegert
mesh_terms: D000577:Amides / Q000494:pharmacology; D001011:Aorta; D000069059:Atorvastatin; D001426:Bacterial Proteins / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology; D054501:Group II Phospholipases A2; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010741:Phospholipases A / Q000096:biosynthesis*; D054467:Phospholipases A2; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020871:RNA Stability; D015854:Up-Regulation
chemical_list: D000577:Amides; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D002070:Butadienes; D022762:CCAAT-Enhancer-Binding Proteins; D005419:Flavonoids; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011758:Pyrroles; C113580:U 0126; C031815:toxB protein, Clostridium difficile; C108830:Y 27632; C012258:mevastatin; D007371:Interferon-gamma; D008148:Lovastatin; D000069059:Atorvastatin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one