title: AZD5363 Inhibits Inflammatory Synergy between Interleukin-17 and Insulin/Insulin-Like Growth Factor 1.
abstract: 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 (IL-17). Insulin and IGF1 are known to enhance IL-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 IL-17-activated nuclear factor-κB pathway through inhibiting glycogen synthase kinase 3β (GSK3β) activity. However, it is unclear whether GSK3α 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 GSK3α and GSK3β. In this study, we investigated IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1), C-C motif ligand 20 (Ccl20), and interleukin-6 (Il-6) in wild-type, GSK3α(-/-), and GSK3β(-/-) 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 IL-17-induced expression of Cxcl1, Ccl20, and Il-6, which was associated with increased phosphorylation of GSK3α and GSK3β in the presence of insulin and IGF1. AZD5363 inhibited the synergy between IL-17 and insulin/IGF1 through reducing phosphorylation of GSK3α and GSK3β by inhibiting Akt function. These findings imply that the cooperative crosstalk of IL-17 and insulin/IGF1 in initiating inflammatory responses may be alleviated by AZD5363.
authors.affiliation: Department of Structural and Cellular Biology, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA ; Department of Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Structural and Cellular Biology, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA ; Department of Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Structural and Cellular Biology, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA ; Department of Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA.
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Structural and Cellular Biology, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA ; Department of Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lambrechts
authors.affiliation: Department of Structural and Cellular Biology, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA ; Department of Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA ; Department of Histology and Embryology, Hebei United University School of Basic Medicine , Tangshan, Hebei Province , China.
authors.forename: Yine
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Structural and Cellular Biology, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA ; Department of Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane Center for Aging, Tulane University School of Medicine , New Orleans, LA , USA.
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
keywords: IGF1; IL-17; inflammation; insulin; obesity; prostate cancer