Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells

Immunol Res. 2007;39(1-3):249-60. doi: 10.1007/s12026-007-0069-0.

Abstract

Host defense against many invading Gram-negative bacteria (GNB) depends on innate immune recognition of endotoxin (lipopolysaccharides, LPS), unique surface glycolipids of GNB. Host responses to endotoxin must be highly sensitive but self-limited. In mammals, optimal sensitivity is achieved by ordered interactions of endotoxin with several different extracellular and cell surface proteins-the LPS-binding protein (LBP), CD14, MD-2, and Toll-like receptor (TLR) 4-reflecting the requirement for specific protein-endotoxin and protein-protein interactions. This complex reaction pathway also provides many ways to attenuate endotoxin-driven inflammation and can explain how differences in endotoxin structure, either intrinsic among GNB or induced by metabolic remodeling, can alter host responsiveness and thus the outcome of host-GNB interactions. Major goals of our research are to better understand: (1) the structural bases of specific host-endotoxin interactions; (2) functional diversity among host endotoxin-binding proteins; and (3) how the actions of various endotoxin-binding proteins are regulated to permit optimal host responses to GNB infection. In addition, the identification of a water-soluble endotoxin:MD-2 complex that, depending on the structure of endotoxin or MD-2, has potent TLR4 agonist or antagonist properties suggests novel pharmacologic approaches to immuno-modulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Endotoxins / immunology
  • Endotoxins / metabolism*
  • Gram-Negative Bacteria / immunology*
  • Gram-Negative Bacteria / metabolism
  • Gram-Negative Bacterial Infections / immunology*
  • Humans
  • Immunity, Innate
  • Lipopolysaccharide Receptors / immunology
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism*
  • Lymphocyte Antigen 96 / immunology
  • Lymphocyte Antigen 96 / metabolism
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Signal Transduction
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism*

Substances

  • Endotoxins
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Membrane Proteins
  • Toll-Like Receptors
  • endotoxin binding proteins