Regulation of kinase cascades and transcription factors by a poly(ADP-ribose) polymerase-1 inhibitor, 4-hydroxyquinazoline, in lipopolysaccharide-induced inflammation in mice.

Abstract

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.

• Authors: Balazs Veres, Balazs Radnai, Ferenc Gallyas Jr, Gabor Varbiro, Zoltan Berente, Erzsebet Osz, Balazs Sumegi
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 310 Issue 1 Pg. 247-55 (Jul 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14999056 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• NF-kappa B
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinazolines
• Quinazolinones
• Transcription Factor AP-1
• Tumor Necrosis Factor-alpha
• 4-hydroxyquinazoline
• Phosphotransferases
• Phosphatidylinositol 3-Kinases
• Mitogen-Activated Protein Kinases

Topics

• Animals
• HeLa Cells
• Humans
• Inflammation (chemically induced, metabolism)
• Kidney (drug effects, enzymology)
• Lipopolysaccharides (pharmacology)
• Liver (drug effects, enzymology)
• Magnetic Resonance Imaging
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Phosphotransferases (metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinazolines (pharmacology)
• Quinazolinones
• Spleen (drug effects, enzymology)
• Transcription Factor AP-1 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)