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Related Experiment Videos

Tolerance to pyrogens

Eugen Zeisberger1, Joachim Roth1

  • 1Physiologisches Institut, Klinikum der Justus Liebig Universität Giessen, Germany.

Annals of the New York Academy of Sciences
|January 26, 1999
PubMed
Summary

Repeated exposure to lipopolysaccharides (LPS) causes tolerance, reducing cytokine production and inflammatory responses. Muramyl dipeptide (MDP) bypasses this tolerance, suggesting distinct immune pathways for different bacterial components.

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Area of Science:

  • Immunology
  • Microbiology
  • Pathophysiology

Background:

  • Repeated exposure to lipopolysaccharides (LPS) from gram-negative bacteria induces tolerance, attenuating inflammatory effects.
  • Muramyl dipeptide (MDP) from gram-positive bacteria does not induce this tolerance.
  • Proinflammatory cytokines mediate many LPS-induced pathophysiologic effects.

Purpose of the Study:

  • To investigate the mechanisms underlying LPS tolerance.
  • To explore the relationship between LPS and MDP in immune tolerance.
  • To examine the role of cytokine production versus responsiveness in LPS tolerance.

Main Methods:

  • Experiments in guinea pigs and rats to assess febrile response and cytokine production.
  • Cross-tolerance experiments using different stimuli for LPS-induced tumor necrosis factor (TNF) and nitric oxide (NO) synthesis.
  • Ex vivo and in vitro studies using monocyte cultures to assess TNF and NO synthesis after LPS restimulation.

Main Results:

  • LPS tolerance is associated with reduced cytokine production, not decreased responsiveness to cytokines.
  • Different stimuli can modify LPS tolerance development by influencing TNF and NO synthesis.
  • MDP can induce febrile responses in LPS-tolerant animals, indicating distinct activation pathways.

Conclusions:

  • LPS tolerance involves reduced cytokine production, with distinct pathways for LPS and MDP.
  • Interferon and granulocyte-macrophage colony-stimulating factor can prevent and reverse diminished cytokine synthesis in LPS-tolerant monocytes.
  • Findings suggest distinct receptors and signaling pathways for LPS and MDP in activating the cytokine cascade.

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