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pubmed:abstractText |
Tumor necrosis factor-? (TNF?) is a multifunctional cytokine involved in the pathophysiology of many chronic inflammatory diseases. TNF? activation of the nuclear factor ?B (NF?B) signaling pathway particularly in macrophages has been implicated in many diseases. We demonstrate here that G-protein coupled receptor kinase-2 and 5 (GRK2 and 5) regulate TNF?-induced NF?B signaling in Raw264.7 macrophages. RNAi knockdown of GRK2 or 5 in macrophages significantly inhibits TNF?-induced I?B? phosphorylation and degradation, NF?B activation, and expression of the NF?B-regulated gene, macrophage inflammatory protein-1?. Consistent with these results, over-expression of GRK2 or 5 enhances TNF?-induced NF?B activity. In addition,we show that GRK2 and 5 interact with I?B? via the N-terminal domain of I?B? and that I?B? isa substrate for GRK2 and 5 in vitro. Furthermore, we also find that GRK5 but not GRK2 phosphorylates I?B? at the same amino acid residues (Ser32/36) as that of IKK?. Interestingly,associated with these results, knockdown of IKK? in Raw264.7 macrophages did not affect TNF?-induced I?B? phosphorylation. Taken together, these results demonstrate that both GRK2 and 5 are important and novel mediators of a non-traditional I?B?-NF?B signaling pathway.
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