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

• Published in: Immunologic research Vol. 39; no. 1-3; pp. 249 - 260
• Main Authors: Gioannini, Theresa L, Weiss, Jerrold P
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.11.2007
• Subjects: Animals; Bacteria; Cells; Endotoxins - immunology; Endotoxins - metabolism; Gram-negative bacteria; Gram-Negative Bacteria - immunology; Gram-Negative Bacteria - metabolism; Gram-Negative Bacterial Infections - immunology; Humans; Immunity, Innate; Immunology; Lipopolysaccharide Receptors - immunology; Lipopolysaccharide Receptors - metabolism; Lipopolysaccharides - immunology; Lipopolysaccharides - metabolism; Lymphocyte Antigen 96 - immunology; Lymphocyte Antigen 96 - metabolism; Membrane Proteins - immunology; Membrane Proteins - metabolism; Proteins; Signal Transduction; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism
• ISSN: 0257-277X; 1559-0755
• DOI: 10.1007/s12026-007-0069-0

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.