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Lipopolysaccharide induces hyporesponsiveness to its own action in raw 2647 cells

Academic Article
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Overview

authors

  • Virca, G. D.
  • Kim, S. Y.
  • Glaser, K. B.
  • Ulevitch, Richard

publication date

  • 1989

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Bacterial endotoxin (lipopolysaccharide, LPS) has the property of inducing hyporesponsiveness or tolerance to its own effects. This phenomenon has been demonstrated in man and experimental animals. The cellular changes that contribute to LPS tolerance are not understood. One mechanism of tolerance could involve a diminished response to LPS by key effector cells such as macrophages. Here we describe experiments designed to determine the mechanism whereby LPS produces a hyporesponsive state to its own effects. Because of the importance of the monokine known as tumor necrosis factor-alpha (TNF-alpha) in mediating many of the diverse effects of LPS, we have studied induction of TNF-alpha at the mRNA and activity level in the murine macrophage-like cell line RAW 264.7. Hyporesponsiveness can be induced by exposure of RAW 264.7 cells to low doses of LPS for more than 6 h prior to challenge with a second, normally stimulatory dose of LPS. This hyporesponsiveness is characterized by a diminished ability of LPS to increase steady state levels of TNF-alpha mRNA, is not due to an increased rate of TNF-alpha mRNA degradation, and is specific for LPS since LPS-pretreated and control cells produce similar amounts of TNF-alpha in response to challenge with heat-killed Staphylococcal aureus. The presence of indomethacin during the primary and/or challenge LPS treatment has no effect on the induction of acquired hyporesponsiveness. Thus, cyclooxygenase products are probably not involved in the development of LPS-induced hyporesponsiveness. These studies provide the basis for a better understanding of the cellular mechanisms that contribute to LPS tolerance.

subject areas

  • Animals
  • Blotting, Northern
  • Cell Line
  • Gene Expression
  • Indomethacin
  • Kinetics
  • Lipopolysaccharides
  • Mice
  • Nucleic Acid Hybridization
  • RNA
  • RNA, Messenger
  • Salmonella
  • Staphylococcus aureus
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

PubMed ID

  • 2480960
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Additional Document Info

start page

  • 21951

end page

  • 21956

volume

  • 264

issue

  • 36

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