[Functional analysis of phospholipase A2 receptor by gene knockout studies].
Phospholipase A2 receptor (PLA2R) 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 A2 (sPLA2-IB). In the present study, we have shown the evidence that a novel type of sPLA2, sPLA2-X, also acts as one of the high-affinity ligands for mouse PLA2R. We then generated PLA2R-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-alpha and IL-1 beta. In situ hybridization analysis revealed that the expression of PLA2R transcript was markedly enhanced in type II alveolar epithelial cells and a subset of splenic lymphocytes in accordance with the elevated expression of sPLA2-IB and TNF-alpha mRNAs during endotoxic shock. In addition, the elevated expression level of TNF-alpha transcript was significantly reduced by the deficiency of PLA2R, suggesting that PLA2R plays a role in the regulation of TNF-alpha expression in these cell types. We then synthesized a specific sPLA2 inhibitor, indoxam, which blocked the binding of sPLA2-IB and X to PLA2R. Indoxam was found to suppress the elevation of the plasma level of TNF-alpha and prolonged the survival of endotoxin-challenged mice. The inhibitory effects of indoxam were abolished by the deficiency of PLA2R, demonstrating the involvement of PLA2R in the progression of endotoxic shock. We also detected and characterized a soluble form of PLA2R protein in the plasma of mouse with anti-PLA2R antibody, and showed its potential role as an endogenous sPLA2 inhibitor. Taken together, a series of studies with PLA2R-knockout mice have elucidated a critical role of PLA2R in the regulation of the development of endotoxic shock.
Yokota
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Shionogi Research Laboratories, Shionogi & Co., Ltd., 5-12-4, Sagisu, Fukushima-ku, Osaka 553-0002, Japan.
D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054501:Group II Phospholipases A2; D054509:Group X Phospholipases A2; D006801:Humans; D007212:Indolizines / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010741:Phospholipases A / Q000502:physiology; D054467:Phospholipases A2; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D054507:Receptors, Phospholipase A2; D012772:Shock, Septic / Q000209:etiology / Q000378:metabolism; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002219:Carbamates; D004791:Enzyme Inhibitors; D007212:Indolizines; C516360:PLA2R1 protein, human; C516357:Pla2r1 protein, mouse; D011956:Receptors, Cell Surface; D054507:Receptors, Phospholipase A2; D014409:Tumor Necrosis Factor-alpha; C119389:indoxam; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054509:Group X Phospholipases A2; C516365:PLA2G10 protein, human; D054467:Phospholipases A2; C516366:Pla2g10 protein, mouse