Modulation of human platelet protein kinase C by endotoxic lipid A.
J Clin Invest
; 82(3): 964-71, 1988 Sep.
Article
em En
| MEDLINE
| ID: mdl-3047171
ABSTRACT
Lipid A is the toxic principle of lipopolysaccharide of gram-negative bacteria, which causes a spectrum of changes in blood cells and vascular cells. We now report that human platelets are directly stimulated by endotoxic lipid A that activates protein kinase C. Rapid phosphorylation of a human platelet protein of Mr 47,000, a marker of protein kinase C activation, accompanies secretion of [14C]serotonin and aggregation triggered by endotoxic lipid A. These events are time and concentration dependent, with phosphorylation reaching maximum in 2 min and the concentration of lipid A causing a 50% effect (EC50) between 12 and 15 microM. Phospholipase C activation in lipid A-stimulated platelets was not observed as judged by a lack of generation of [3H]diacylglycerol in [3H]arachidonic acid-labeled platelets and a lack of generation of [32P]-phosphatidic acid in 32PO4-labeled platelets. Lipid A did not induce formation of TXA2 as measured by radioimmunoassay for TXB2. The stimulation of human platelets and activation of protein kinase C by endotoxic lipid A was blocked by lipid X, a structural precursor of lipid A. Lipid X also blocked the stimulation of human platelets by phorbol 12-myristate 13-acetate, suggesting that lipid A, lipid X and phorbol ester share reactive site(s) on the human platelet membrane. Although lipid X inhibited thrombin-induced phosphorylation of P47 it did not suppress secretion of [14C]serotonin, indicating the role of protein kinase C-independent pathways in platelet stimulation by thrombin. The inhibitory effect of lipid X did not involve generation of cyclic AMP in human platelet membrane preparations. These results indicate that human platelets are stimulated by endotoxic lipid A, a naturally occurring biologic modifier of protein kinase C. Due to the widespread presence of this enzyme in blood cells, vascular cells, and neurons, its modulation by lipid A may represent a significant mechanism underlying hematologic and circulatory derangements observed in endotoxic shock in humans.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Plaquetas
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Proteína Quinase C
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Endotoxinas
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Lipídeo A
Limite:
Humans
Idioma:
En
Ano de publicação:
1988
Tipo de documento:
Article