AZD5363 inhibits inflammatory synergy between interleukin-17 and insulin/insulin-like growth factor 1

In the United States, one-third of population is affected by obesity and almost 29 million people are suffering from type 2 diabetes. Obese people have elevated serum levels of insulin, insulin-like growth factor 1 (IGF1), and interleukin-17 (11,17). Insulin and IGF1 are known to enhance I I,17-induced expression of inflammatory cytokines and chemokines, which may contribute to the chronic inflammatory status observed in obese people. We have previously demonstrated that insulin/IGF1 signaling pathway crosstalks with 11,17-activated nuclear factor-KB pathway through inhibiting glycogen synthase kinase 313 (GSK31) activity. However, it is unclear whether GSK3 alpha also plays a role and whether this crosstalk can be manipulated by AZD5363, a novel pan-Akt inhibitor that has been shown to increase glycogen synthase kinase 3 activity through reducing phosphorylation of GSK3 alpha and GSK31. In this study, we investigated 11,17-induced expression of C-X-C motif ligand 1 (Cxcl1), CC motif ligand 20 (Cc120), and interleukin-6 (11-6) in wild-type, GSK3 alpha(-/-), and GSK3 beta(-/-)mouse embryonic fibroblast cells as well as in mouse prostate tissues by real-time quantitative PCR. We examined the proteins involved in the signaling pathways by Western blot analysis. We found that insulin and IGF1 enhanced 11,17-induced expression of Cxcll, Cc120, and 11-6, which was associated with increased phosphorylation of GSK3a and GSK31 in the presence of insulin and IGF1. AZD5363 inhibited the synergy between 1L17 and insulin/IGF1 through reducing phosphorylation of GSK3 alpha and GSK3 beta by inhibiting Akt function. These findings imply that the cooperative crosstalk of 11,17 and insulin/IGF1 in initiating inflammatory responses may be alleviated by AZD5363.