Myeloid-specific GPCR kinase-2 negatively regulates NF-κB1p105-ERK pathway and limits endotoxemic shock in mice
✍ Scribed by Sonika Patial; Yogesh Saini; Sitaram Parvataneni; Daniel M. Appledorn; Gerald W. Dorn II; John J. LaPres; Andrea Amalfitano; Patricia Senagore; Narayanan Parameswaran
- Book ID
- 102884049
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 570 KB
- Volume
- 226
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
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 (GRK2^fl/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 GRK2^fl/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. J. Cell. Physiol. 226: 627–637, 2011. © 2010 Wiley‐Liss, Inc.