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OtherIMMUNOPHARMACOLOGY

Modulation of Mouse Endotoxin Shock by Inhibition of Phosphatidylcholine-Specific Phospholipase C

Klaus Tschaikowsky, J. Schmidt and M. Meisner
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 800-804;
Klaus Tschaikowsky
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J. Schmidt
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M. Meisner
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Abstract

During Gram-negative bacterial infections, lipopolysaccharide (LPS) interacts with monocyte/macrophage receptors, resulting in a host defense response. Activation of intracellular signal transduction pathways implicating various protein kinase and phospholipases is crucial in activating the transcription of genes encoding proinflammatory cytokines and inducible nitric oxide synthase (iNOS). In this article, we demonstrate that in mouse, endotoxin shock activation of phosphatidylcholine-specific phospholipase C (PC-PLC) plays a major role in controlling the inflammatory response. Inhibition of PC-PLC by the specific inhibitor tricyclodecan-9-yl-xanthogenate (D609) before LPS reduced the release of interleukin-1β, interleukin-6 and nitric oxide (NO) in vivo. In contrast, tumor necrosis factor-α serum levels were not altered by the pretreatment with D609. Consequently, survival from endotoxin shock of D609-treated animals was significantly improved compared with control animals (45% vs. 20%). Thus, inhibition of PC-PLC can reduce the inflammatory response to LPS and may serve as a novel approach to therapy of sepsis.

Footnotes

  • Send reprint requests to: Dr. K. Tschaikowsky, Department of Anesthesiology, University of Erlangen-Nürnberg, Krankenhausstr. 12, D-91054 Erlangen, Germany. E-mail:klaus.tschaikowsky{at}rzmail.uni-erlangen.de

  • ↵1 This work was supported by grants from the Bundesministerium für Bildung und Forschung and the Zentrum für Klinische Forschung der Friedrich-Alexander-Universität Erlangen-Nürnberg.

  • Abbreviations:
    D609
    tricyclodecan-9-yl-xanthogenate
    PC-PLC
    phosphatidylcholine-specific phospholipase C
    SMase
    sphingomyelinase
    LPS
    lipopolysaccharide
    IL-1β
    interleukin 1-β
    IL-6
    interleukin 6
    TNF-α
    tumor necrosis factor-α
    NO
    nitric oxide
    iNOS
    inducible nitric oxide synthase
    NF-κB
    nuclear factor-κB
    • Received September 23, 1997.
    • Accepted December 29, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherIMMUNOPHARMACOLOGY

Modulation of Mouse Endotoxin Shock by Inhibition of Phosphatidylcholine-Specific Phospholipase C

Klaus Tschaikowsky, J. Schmidt and M. Meisner
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 800-804;

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OtherIMMUNOPHARMACOLOGY

Modulation of Mouse Endotoxin Shock by Inhibition of Phosphatidylcholine-Specific Phospholipase C

Klaus Tschaikowsky, J. Schmidt and M. Meisner
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 800-804;
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