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-κB (NF-κB) 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-κB- and AP-1 transcription factor activation, are mediated, at least partially, through the regulation of the PI3-kinase/Akt pathway and MAP kinase cascades.
Footnotes
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This work was supported by Hungarian Science Foundation T034320, Ministry of Health and Welfare ETT 559/2003, Biotech BIO-00004/2002, Hungarian Ministry of Education 0167/2001 and 0168/2001, Bolyai BO/00166/01, BO/00170/01, and by Welcome Trust 059917.
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DOI: 10.1124/jpet.104.065151.
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ABBREVIATIONS: PARP, poly(ADP-ribose) polymerase; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-α; IL, interleukin; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; AP-1, activator protein 1; NF-κB, nuclear factor-κB; PI3, phosphatidylinositol 3; MRI, magnetic resonance imaging; 4-HQN, 4-hydroxyquinazoline; GSK, glycogen synthase kinase.
- Received January 6, 2004.
- Accepted March 3, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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