G-protein coupled receptor kinase 5 mediates lipopolysaccharide-induced NFκB activation in primary macrophages and modulates inflammation in vivo in mice

J Cell Physiol. 2011 May;226(5):1323-33. doi: 10.1002/jcp.22460.


G-protein coupled receptor kinase-5 (GRK5) is a serine/threonine kinase discovered for its role in the regulation of G-protein coupled receptor signaling. Recent studies have shown that GRK5 is also an important regulator of signaling pathways stimulated by non-GPCRs. This study was undertaken to determine the physiological role of GRK5 in Toll-like receptor-4-induced inflammatory signaling pathways in vivo and in vitro. Using mice genetically deficient in GRK5 (GRK5(-/-) ) we demonstrate here that GRK5 is an important positive regulator of lipopolysaccharide (LPS, a TLR4 agonist)-induced inflammatory cytokine and chemokine production in vivo. Consistent with this role, LPS-induced neutrophil infiltration in the lungs (assessed by myeloperoxidase activity) was markedly attenuated in the GRK5(-/-) mice compared to the GRK5(+/+) mice. Similar to the in vivo studies, primary macrophages from GRK5(-/-) mice showed attenuated cytokine production in response to LPS. Our results also identify TLR4-induced NFκB pathway in macrophages to be selectively regulated by GRK5. LPS-induced IκBα phosphorylation, NFκB p65 nuclear translocation, and NFκB binding were markedly attenuated in GRK5(-/-) macrophages. Together, our findings demonstrate that GRK5 is a positive regulator of TLR4-induced IκBα-NFκB pathway as well as a key modulator of LPS-induced inflammatory response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Female
  • G-Protein-Coupled Receptor Kinase 5 / deficiency
  • G-Protein-Coupled Receptor Kinase 5 / drug effects*
  • G-Protein-Coupled Receptor Kinase 5 / genetics
  • G-Protein-Coupled Receptor Kinase 5 / metabolism
  • I-kappa B Proteins / metabolism
  • Inflammation / chemically induced
  • Inflammation / enzymology*
  • Inflammation / immunology
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / pharmacology*
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / immunology
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / enzymology
  • Macrophages, Peritoneal / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Neutrophil Infiltration / drug effects
  • Phosphorylation
  • Signal Transduction / drug effects
  • Time Factors
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / metabolism


  • Cytokines
  • I-kappa B Proteins
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • lipopolysaccharide, Escherichia coli O111 B4
  • NF-KappaB Inhibitor alpha
  • G-Protein-Coupled Receptor Kinase 5
  • Grk5 protein, mouse