Heterotrimeric Gi/Go proteins modulate endothelial TLR signaling independent of the MyD88-dependent pathway

Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2246-53. doi: 10.1152/ajpheart.01194.2010. Epub 2011 Sep 23.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Enzyme Activation
  • GTP-Binding Protein alpha Subunit, Gi2 / genetics
  • GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
  • Genes, Reporter
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Immunity, Innate* / drug effects
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Lipopolysaccharides / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism
  • Myeloid Differentiation Factor 88 / metabolism*
  • NF-kappa B / metabolism
  • Poly I-C / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction* / drug effects
  • TNF Receptor-Associated Factor 6 / metabolism
  • Time Factors
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptors / metabolism*
  • Transfection

Substances

  • Lipopolysaccharides
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • TLR2 protein, human
  • TLR3 protein, human
  • TLR4 protein, human
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 2
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Interleukin-1 Receptor-Associated Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • GNAI2 protein, human
  • GTP-Binding Protein alpha Subunit, Gi2
  • Poly I-C