Fig. 3. Detection of lipid A endotoxin by animal cells and function of the signaling receptor TLR-4 in innate immunity. The above paradigm is based mainly upon studies of human, mouse and hamster cells (23-26). The TLR-4 receptor may be oligomerized upon binding of lipid A. As indicated by the upper arrow, cell activation can occur without CD14, but requires several orders of magnitude more lipid A. Overproduction of TNF-a and TLI-b during a severe infection can damage small blood vessals, causing fluid leakage and shock. Synthetic lipid A analogues and certain precursors are potent endotoxin antagonists via TLR-4 (22,26,66,67).