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

Sonika Patial, Yogesh Saini, Sitaram Parvataneni, Daniel M. Appledorn, Gerald W. Dorn, John J. LaPres, Andrea Amalfitano, Patricia Senagore, Narayanan Parameswaran

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 (GRK2δmye). GRK2δmye 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 GRK2δmye 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 GRK2δmye macrophages compared to GRK2fl/fl cells and importantly, inhibition of the p105 and ERK pathways in the GRK2δmye 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.

Original languageEnglish
Pages (from-to)627-637
Number of pages11
JournalJournal of Cellular Physiology
Volume226
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Dive into the research topics of 'Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice'. Together they form a unique fingerprint.

Cite this