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

✍ Scribed by Sonika Patial; Shipra Shahi; Yogesh Saini; Taehyung Lee; Nandakumar Packiriswamy; Daniel M. Appledorn; John J. LaPres; Andrea Amalfitano; Narayanan Parameswaran

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 625 KB
• Volume: 226
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.22460

✦ Synopsis

Abstract

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. J. Cell. Physiol. 226: 1323–1333, 2011. © 2010 Wiley‐Liss, Inc.