Regulation of kinase cascades and transcription factors by a poly(ADP-ribose) polymerase-1 inhibitor, 4-hydroxyquinazoline, in lipopolysaccharide-induced inflammation in mice.
Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is involved in numerous pathophysiological conditions. Because PARP-1 knockout mice are resistant to endotoxin-induced shock and inhibitors of the enzyme were reported to have similar beneficial properties, we investigated the effect of 4-hydroxyquinazoline (4-HQN), a potent PARP-1 inhibitor, on the modulation of kinase cascades and the regulation of transcription factors in a rodent septic shock model. T2-weighted magnetic resonance imaging showed the pattern of anatomical localization of the inflammatory response in bacterial lipopolysaccharide (LPS)-treated mice and the anti-inflammatory effect of the PARP-1 inhibitor. We have found that 4-HQN activated the phosphatidylinositol 3 (PI3)-kinase/Akt pathway in lung, liver, and spleen, and down-regulated two elements of the MAP kinase system. Namely, it dramatically attenuated the activation of the LPS-induced extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase in a tissue-specific manner. Furthermore, phosphorylation of p90RSK, a downstream target of ERK1/2, showed a similar pattern of down-regulation as did the phosphorylation of ERK1/2 and p38 after LPS and 4-HQN treatment. As a consequence of the aforementioned effects on the kinase pathways, 4-HQN decreased the activation of transcription factor nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) in LPS-induced endotoxic shock. Our results provide evidence for the first time that the beneficial effects of PARP inhibition in endotoxic shock, such as attenuation of NF-kappaB- and AP-1 transcription factor activation, are mediated, at least partially, through the regulation of the PI3-kinase/Akt pathway and MAP kinase cascades.
Veres
Balazs
B
Department of Biochemistry and Medicinal Chemistry, Faculty of Medicine, University of Pécs, Hungary.
Radnai
Balazs
B
Gallyas
Ferenc
F
Varbiro
Gabor
G
Berente
Zoltan
Z
Osz
Erzsebet
E
Sumegi
Balazs
B
D000818:Animals; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D013154:Spleen / Q000187:drug effects / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C061339:4-hydroxyquinazoline; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases