Abstract
The innate immune recognition of bacterial lipopolysaccharide (LPS) is mediated by Toll-like receptor 4 (TLR4) and results in activation of proinflammatory signaling including NF-κB and MAPK pathways. Heterotrimeric G proteins have been previously implicated in LPS signaling in macrophages and monocytes. In the present study, we show that pertussis toxin sensitive heterotrimeric G proteins (Gα(i/o)) are involved in the activation of MAPK and Akt downstream of TLR2, TLR3, and TLR4 in endothelial cells. Gα(i/o) are also required for full activation of interferon signaling downstream of TLR3 and TLR4 but are not required for the activation of NF-κB. We find that Gα(i/o)-mediated activation of the MAPK is independent of the canonical MyD88, interleukin-1 receptor-associated kinase, and tumor necrosis factor receptor-associated factor 6 signaling cascade in LPS-stimulated cells. Taken together, the data presented here suggest that heterotrimeric G proteins are widely involved in TLR pathways along a signaling cascade that is distinct from MyD88-TRAF6.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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Enzyme Activation
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GTP-Binding Protein alpha Subunit, Gi2 / genetics
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GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
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Genes, Reporter
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / immunology
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Human Umbilical Vein Endothelial Cells / metabolism*
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Humans
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Immunity, Innate* / drug effects
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Lipopolysaccharides / pharmacology
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Mitogen-Activated Protein Kinases / metabolism
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Myeloid Differentiation Factor 88 / metabolism*
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NF-kappa B / metabolism
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Poly I-C / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Signal Transduction* / drug effects
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TNF Receptor-Associated Factor 6 / metabolism
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Time Factors
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 3 / metabolism
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Toll-Like Receptor 4 / metabolism
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Toll-Like Receptors / metabolism*
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Transfection
Substances
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Lipopolysaccharides
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MYD88 protein, human
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Myeloid Differentiation Factor 88
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NF-kappa B
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TLR2 protein, human
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TLR3 protein, human
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TLR4 protein, human
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Interleukin-1 Receptor-Associated Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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GNAI2 protein, human
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GTP-Binding Protein alpha Subunit, Gi2
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Poly I-C