TLR4:MD2:LPS:CD14 recruits TRAM Endocytosis of TRAM Association of LBP with LPS Endocytosis of TLR4:MD2:LPS:CD14 Transfer of LPS onto TLR4 MAL(TIRAP) binds PIP2-rich regions in the plasma membrane CD14:LPS binds CR3 PathwayStep6777 PathwayStep6778 PathwayStep6779 PathwayStep6770 PathwayStep6776 PathwayStep6775 PathwayStep6774 PathwayStep6773 PathwayStep6797 Toll Like Receptor 4 (TLR4) Cascade Authored: de Bono, B, 2005-08-16 10:54:15 Edited: Shamovsky, V, 2010-11-15 GENE ONTOLOGYGO:0008063 Reactome Database ID Release 43166016 Reactome, http://www.reactome.org ReactomeREACT_6894 Reviewed: Gay, NJ, 2006-04-24 16:48:17 Reviewed: Gillespie, ME, 2010-11-30 Toll-like Receptor 4 is a Microbe Associated Molecular Pattern receptor well known for it's sensitivity to Bacterial Lipopolysaccharides (LPS). LPS is assembled within diverse Gram-negative bacteria, many of which are human or plant pathogens. It is a component of the outer membrane of Gram-negative bacteria and consists of lipid A, a core polysaccharide and an O-polysaccharide of variable length (often more than 50 monosaccharide units). LPS is a potent activator of the innate immune response in humans, causing reactions including fever, headache, nausea, diarrhoea, changes in leukocyte and platelet counts, disseminated intravascular coagulation, multiorgan failure, shock and death. All these reactions are induced by cytokines and other endogenous mediators which are produced after interaction of LPS with the humoral and cellular targets of the host. In macrophages and dendritic cells, LPS-mediated activation of TLR4 triggers the biosynthesis of diverse mediators of inflammation, such as TNF-alpha and IL6, and activates the production of co-stimulatory molecules required for the adaptive immune response. In mononuclear and endothelial cells, LPS also stimulates tissue factor production. These events are desirable for clearing local infections, but when these various mediators and clotting factors are overproduced, they can damage small blood vessels and precipitate shock accompanied by disseminated intravascular coagulation and multiple organ failure. Transfer of LPS from LBP carrier to CD14 Activated TLR4 signalling