Abstract
Septic shock induced by lipopolysaccharide (LPS) triggering of cytokine production from monocytes/macrophages is a major cause of morbidity and mortality. The major monocyte/macrophage LPS receptor is the glycosylphosphatidylinositol (GPI)-anchored glycoprotein CD14. Here we demonstrate that CD14 coimmunoprecipitates with Gi/Go heterotrimeric G proteins. Furthermore, we demonstrate that heterotrimeric G proteins specifically regulate CD14-mediated, LPS-induced mitogen-activated protein kinase (MAPK) activation and cytokine production in normal human monocytes and cultured cells. We report here that a G protein binding peptide protects rats from LPS-induced mortality, suggesting a functional linkage between a GPI-anchored receptor and the intracellular signaling molecules with which it is physically associated.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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GTP-Binding Proteins / isolation & purification
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GTP-Binding Proteins / physiology*
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Humans
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Intercellular Signaling Peptides and Proteins
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Lipopolysaccharide Receptors / drug effects
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Lipopolysaccharide Receptors / isolation & purification
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Lipopolysaccharide Receptors / physiology*
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Lipopolysaccharides / pharmacology*
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Lipopolysaccharides / toxicity
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Monocytes / drug effects
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Monocytes / metabolism
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Peptides
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Rats
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Recombinant Fusion Proteins / physiology
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Shock, Septic / etiology
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Shock, Septic / physiopathology*
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Shock, Septic / prevention & control
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Transfection
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Virulence Factors, Bordetella / pharmacology
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Wasp Venoms / pharmacology
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Wasp Venoms / therapeutic use
Substances
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Intercellular Signaling Peptides and Proteins
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Peptides
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Recombinant Fusion Proteins
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Virulence Factors, Bordetella
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Wasp Venoms
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mastoparan
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GTP-Binding Proteins