Statins potentiate the IFN-gamma-induced upregulation of group IIA phospholipase A2 in human aortic smooth muscle cells and HepG2 hepatoma cells.
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.
Menschikowski
Mario
M
Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus, Institut für Klinische Chemie und Laboratoriumsmedizin, Germany. menschik@rcs.urz.tu-dresden.de
Hagelgans
Albert
A
Heyne
Ben
B
Hempel
Ute
U
Neumeister
Volker
V
Goez
Peter
P
Jaross
Werner
W
Siegert
Gabriele
G
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
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