Endotoxin antagonism: conceptual basis and therapeutic potential.
Since antiquity, physicians have beheld infections with deep consternation, knowing that a local lesion can have horrific systemic effects. Even in modern times, these effects have generally been impossible to control. Until recently, their ultimate cause was not well understood. Now, within the space of only a few years, the proximal cause of sepsis has been identified. Paralogous members of the Toll-like receptor (TLR) family sense infection and ignite the systemic inflammatory reaction that is known as sepsis. The question at hand has become a practical one: can this understanding be exploited to a therapeutic advantage?
Beutler
Bruce
B
The Scripps Research Institute, 10550 N, Torrey Pines Road, La Jolla, CA 92037, USA. bruce@scripps.edu
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D001424:Bacterial Infections / Q000188:drug therapy*; D016207:Cytokines / Q000502:physiology; D029721:Drosophila Proteins / Q000502:physiology; D004331:Drosophila melanogaster / Q000378:metabolism / Q000382:microbiology; D015195:Drug Design; D004351:Drug Resistance; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology; D018123:Receptors, Interleukin / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000502:physiology; D053724:Receptors, Interleukin-18; D018805:Sepsis / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D029721:Drosophila Proteins; D004731:Endotoxins; D005938:Glucocorticoids; C508572:IL18R1 protein, human; C508573:Il18r1 protein, mouse; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C499312:Myd88 protein, Drosophila; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; C068721:Tl protein, Drosophila; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; C495341:tehao protein, Drosophila