G-protein coupled receptor kinase-5 mediates Toll-like receptor-4-induced NFκB activation in primary macrophages and in vivo in mice (94.11)

Abstract

Toll-like receptor-4 (TLR4) activated by lipopolysaccharide (LPS) is involved in a number of inflammatory diseases, in part via activation of NFκB pathway. G-protein coupled receptor kinase-5 (GRK5), a serine-threonine kinase originally discovered for its role in desensitization of G-protein coupled receptors has recently been shown to regulate NFκB pathway stimulated by non-GPCRs. This study was undertaken to determine the potential role of GRK5 in inflammatory signaling in primary macrophages and in vivo using GRK5 knockout (KO) mice. We demonstrate here that TLR4-induced IκBα-NFκB pathway is selectively inhibited in primary macrophage from GRK5 KO mice compared to cells from GRK5 wild type (WT) mice. Consistent with the effects on the NFκB pathway, LPS-induced production of many inflammatory cytokines/chemokines (including Interleukin-2, -3, -4, -5, -12, -17, MCP-1, IFNγ, KC, GMCSF and Eotaxin) are inhibited in GRK5 KO macrophages. Confirming this in vitro data, LPS-induced cytokines/chemokines levels in the plasma are also significantly inhibited in the GRK5 KO mice in vivo. Associated with these effects LPS-mediated liver injury is markedly decreased in the GRK5 KO mice. Taken together, our findings demonstrate that GRK5 acts as a positive regulator of TLR4 signaling in vivo and further suggest that these findings could have potential implications for drug development in inflammatory diseases.