Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice.
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.
Patial
Sonika
S
Department of Physiology and Division of Pathology, Michigan State University, East Lansing, Michigan 48824, USA.
Saini
Yogesh
Y
Parvataneni
Sitaram
S
Appledorn
Daniel M
DM
Dorn
Gerald W
GW
Lapres
John J
JJ
Amalfitano
Andrea
A
Senagore
Patricia
P
Parameswaran
Narayanan
N
D000818:Animals; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D022423:Myeloid Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D012772:Shock, Septic / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D016019:Survival Analysis
C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D016753:Interleukin-10; C073701:Nfkb1 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases