Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice

J Cell Physiol. 2011 Mar;226(3):627-37. doi: 10.1002/jcp.22384.

Abstract

G-protein-coupled receptor kinase 2 (GRK2) is a member of a kinase family originally discovered for its role in the phosphorylation and desensitization of G-protein-coupled receptors. It is expressed in high levels in myeloid cells and its levels are altered in many inflammatory disorders including sepsis. To address the physiological role of myeloid cell-specific GRK2 in inflammation, we generated mice bearing GRK2 deletion in myeloid cells (GRK2▵mye). GRK2▵mye mice exhibited exaggerated inflammatory cytokine/chemokine production, and organ injury in response to lipopolysaccharide (LPS, a TLR4 ligand) when compared to wild-type littermates (GRK2fl/fl). Consistent with this, peritoneal macrophages from GRK2▵mye mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4-induced NF-κB1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NF-κB1p105-MEK-ERK pathway is significantly enhanced in the GRK2▵mye macrophages compared to GRK2fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2▵mye macrophages, limits the enhanced production of LPS-induced cytokines/chemokines. Taken together, our studies reveal previously undescribed negative regulatory role for GRK2 in TLR4-induced p105-ERK pathway as well as in the consequent inflammatory cytokine/chemokine production and endotoxemia in mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemokine CCL3 / metabolism
  • Endotoxemia / complications
  • Endotoxemia / enzymology*
  • Endotoxemia / pathology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • Inflammation / complications
  • Inflammation / enzymology
  • Inflammation / pathology
  • Interleukin-10 / metabolism
  • Interleukin-12 Subunit p40 / metabolism
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System* / drug effects
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Models, Biological
  • Myeloid Cells / drug effects
  • Myeloid Cells / enzymology*
  • Myeloid Cells / pathology
  • NF-kappa B p50 Subunit / antagonists & inhibitors
  • NF-kappa B p50 Subunit / metabolism*
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Organ Specificity / drug effects
  • Shock, Septic / complications
  • Shock, Septic / enzymology*
  • Shock, Septic / pathology
  • Survival Analysis

Substances

  • Ccl3 protein, mouse
  • Chemokine CCL3
  • Interleukin-12 Subunit p40
  • Lipopolysaccharides
  • NF-kappa B p50 Subunit
  • Interleukin-10
  • Nfkb1 protein, mouse
  • G-Protein-Coupled Receptor Kinase 2
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Mitogen-Activated Protein Kinase Kinases