Molecular mechanisms responsible for endotoxin tolerance

Prog Clin Biol Res. 1998:397:209-15.

Abstract

Bacterial lipopolysaccharide endotoxin (LPS) is a potent activator of a number of inflammatory genes, including interleukin-1 (IL-1). IL-1 and other cytokines such as tumor necrosis factor alpha (TNF alpha) are essential mediators in inducing severe sepsis syndromes (SS). Major cellular targets of LPS are blood or tissue leukocytes, such as macrophages and neutrophils. These cells can respond and adapt to LPS, the latter phenomenon is known as LPS tolerance. In animals, LPS tolerance is a highly effective mechanism of protection against the lethal syndrome of severe sepsis. Two models are used to investigate the molecular basis of LPS tolerance. The first model employs blood leukocytes isolated from patients with SS. The second model employs the promonocytic cell line, THP-1 in vitro. In the SS model, LPS tolerance of involves repression at the level of IL-1 beta mRNA. Suppression of IL-1 beta mRNA is under the control of a labile repressor protein. In contrast to suppression of IL-1 beta, mRNA is under the control of a labile repressor protein. In contrast to suppression of IL-1 beta, there is increased expression of the Type 2 IL-1 receptor mRNA and protein in leukocytes from patients with SS. The THP-1 model of LPS tolerance also involves repression of LPS induction of IL-1 beta gene expression. The repression of THP-1 cell IL-1 beta expression is at the level of transcription, and like the SS model is under the control of a labile protein. LPS tolerance in both models is stimulus-specific. We further find that transcription factors such as NF kappa B and AP-1 may participate in regulating LPS tolerance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Drug Tolerance / genetics
  • Gene Expression Regulation / drug effects*
  • Humans
  • Interleukin-1 / genetics
  • Leukocytes / drug effects*
  • Leukocytes / metabolism
  • Lipopolysaccharides / pharmacology*
  • Models, Immunological
  • Monocytes / drug effects
  • Neutrophils / drug effects
  • Phenotype
  • Shock, Septic / blood
  • Systemic Inflammatory Response Syndrome / blood
  • Transfection

Substances

  • Interleukin-1
  • Lipopolysaccharides