Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells.
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.
Gioannini
Theresa L
TL
The Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 2501 Crosspark Rd, Coralville, Iowa City, IA 52241, USA.
Weiss
Jerrold P
JP
D000818:Animals; D004731:Endotoxins / Q000276:immunology / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000276:immunology* / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D051218:Lymphocyte Antigen 96 / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008565:Membrane Proteins; D051193:Toll-Like Receptors; C025357:endotoxin binding proteins