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(Delta mye)). GRK2(Delta 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 (GRK2(fl/fl)). Consistent with this, peritoneal macrophages from GRK(2 Delta mye) mice showed enhanced inflammatory cytokine levels when stimulated with LPS. Our results further identify TLR4-induced NF-kappa B1p105-ERK pathway to be selectively regulated by GRK2. LPS-induced activation of NF-kappa B1p105-MEK-ERK pathway is significantly enhanced in the GRK2(Delta mye) macrophages compared to GRK2(fl/f)l cells and importantly, inhibition of the p105 and ERK pathways in the GRK2(Delta 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. J. Cell. Physiol. 226: 627-637, 2011. (C) 2010 Wiley-Liss, Inc.