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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Regulation of Kinase Cascades and Transcription Factors by a Poly(ADP-Ribose) Polymerase-1 Inhibitor, 4-Hydroxyquinazoline, in Lipopolysaccharide-Induced Inflammation in Mice

Balazs Veres, Balazs Radnai, Ferenc Gallyas Jr., Gabor Varbiro, Zoltan Berente, Erzsebet Osz and Balazs Sumegi
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 247-255; DOI: https://doi.org/10.1124/jpet.104.065151
Balazs Veres
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Balazs Radnai
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Ferenc Gallyas Jr.
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Gabor Varbiro
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Zoltan Berente
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Erzsebet Osz
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Balazs Sumegi
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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

  • 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.

  • DOI: 10.1124/jpet.104.065151.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Regulation of Kinase Cascades and Transcription Factors by a Poly(ADP-Ribose) Polymerase-1 Inhibitor, 4-Hydroxyquinazoline, in Lipopolysaccharide-Induced Inflammation in Mice

Balazs Veres, Balazs Radnai, Ferenc Gallyas, Gabor Varbiro, Zoltan Berente, Erzsebet Osz and Balazs Sumegi
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 247-255; DOI: https://doi.org/10.1124/jpet.104.065151

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Regulation of Kinase Cascades and Transcription Factors by a Poly(ADP-Ribose) Polymerase-1 Inhibitor, 4-Hydroxyquinazoline, in Lipopolysaccharide-Induced Inflammation in Mice

Balazs Veres, Balazs Radnai, Ferenc Gallyas, Gabor Varbiro, Zoltan Berente, Erzsebet Osz and Balazs Sumegi
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 247-255; DOI: https://doi.org/10.1124/jpet.104.065151
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