Phospholipase A
2 receptor (PLA
2R) is a type I transmembrane glycoprotein related to the C-type animal lectin family and mediates a variety of biological responses elicited by group IB secretory phospholipase A
2 (sPLA
2-IB). In the present study, we have shown the evidence that a novel type of sPLA
2, sPLA
2-X, also acts as one of the high-affinity ligands for mouse PLA
2R. We then generated PLA
2R-deficient mice and found that the knockout mice exhibited the resistance to an endotoxic shock with reduced plasma levels of proinflammatory cytokines, such as TNF-α and IL-1β. In situ hybridization analysis revealed that the expression of PLA
2R transcript was markedly enhanced in type II alveolar epithelial cells and a subset of splenic lymphocytes in accordance with the elevated expression of sPLA
2-IB and TNF-α mRNAs during endotoxic shock. In addition, the elevated expression level of TNF-α transcript was significantly reduced by the deficiency of PLA
2R, suggesting that PLA
2R plays a role in the regulation of TNF-α expression in these cell types. We then synthesized a specific sPLA
2 inhibitor, indoxam, which blocked the binding of sPLA
2-IB and X to PLA
2R. Indoxam was found to suppress the elevation of the plasma level of TNF-α and prolonged the survival of endotoxin-challenged mice. The inhibitory effects of indoxam were abolished by the deficiency of PLA
2R, demonstrating the involvement of PLA
2R in the progression of endotoxic shock. We also detected and characterized a soluble form of PLA
2R protein in the plasma of mouse with anti-PLA
2R antibody, and showed its potential role as an endogenous sPLA
2 inhibitor. Taken together, a series of studies with PLA
2R-knockout mice have elucidated a critical role of PLA
2R in the regulation of the development of endotoxic shock.
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