Toll—like receptor 4, a novel signal transducer for lipopolysaccharide

Lipopolysaccharide (LPS), or endotoxin, is the major component of the outer surface of gram-negative bacteria. LPS is a potent activator of the cells of the immune and inflammation systems, including macrophages, monocytes and endothelial cells, and contributes to systemic changes seen in septic shock.1,2 It has long been believed that LPS is responsible for several fatal consequences of gram-negative infection. Cell activation by LPS constitutes the first step in the cascade of events believed to lead to the manifestation of gram-negative sepsis, which results in approximately 20 000 annual deaths in the United States3 and 30% mortality rate of known cases in China.Therefore, the action mechanism of LPS is one of the most important problems in the research field of immunity, inflammation and surgery. Researchers have investigated the mechanism of cell activity and injury of LPS for a long time. In 1990, CD14，the glycosyl-phosphatidylinositol (GPI)-linked plasma membrane protein, was identified as a proximal LPS receptor on the cell surface of macrophages, and it was suggested that CD14 and LBP (lipopolysaccharide binding protein) played an important role in the effect mechanism of LPS. CD14 seemed to receive LPS via transfer from the plasma protein LBP. Then, two action patterns were recognized. CD14 positive cells, such as macrophages and leukocytes, were activated after LPS combined with LBP and interacted with CD14. But, CD14 negative cells (for example, endothelial cells), were activated through other receptors that we did not know of in the cell surface after LPS, LBP and soluble CD14 (sCD14) combined with the compounds. However, there are some questions to be answered. Firstly, because CD14 lacks cytoplasmic doman, it is unlikely to act as the transducer. Secondly, the action pattern of LPS through CD14 and LBP may be in dose-dependent mode, but, in conditions of high dosage and long exposure to LPS action, CD14 and LBP do not play an important role in LPS activation effect. Finally, for CD14 negative cells, the receptor combined LPS-LBP-sCD14 compound has not yet been identified. Some details indicated that a “co-receptor” for LPS signal transduction must exist. Although standard biochemical approaches, transfection assay, and immunologic tacties were all employed to search for this co-receptor, it has not yet been found. The find of Toll-like receptor 4 (TLR4) provides a new opportunity to study the mechanism of LPS action.

Toll-like receptor 4, a novel signal transducer for lipopolysaccharide