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.
Highlights
Interleukin-17 (IL-17 or IL-17A) is an inflammatory cytokine [1]
We found that insulin and insulin-like growth factor 1 (IGF1) enhanced IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1), CC motif ligand 20 (Ccl20), and Il-6, which was associated with increased phosphorylation of GSK3α and glycogen synthase kinase 3β (GSK3β) in the presence of insulin and IGF1
In the wild-type mouse embryonic fibroblast (MEF) cells, insulin or IGF1 alone treatment led to increased levels of phosphorylated Akt (P-Akt), P-GSK3α, and P-GSK3β (Figures 1A,B)
Summary
Interleukin-17 (IL-17 or IL-17A) is an inflammatory cytokine [1] It can activate nuclear factor-κB (NF-κB) activator 1 (Act1) through similar expression to fibroblast growth factor genes, IL17 receptors, and Toll–IL-1R (SEFIR) domains, upon its binding to a heterodimer of IL-17RA/IL-17RC receptor complex [2,3,4,5,6]. The polyubiquitinated TRAF6 triggers transforming growth factor-β-activated kinase 1 (TAK1) and subsequently IκB kinase (IKK) complex, which in turn leads to activation of NF-κB pathway that induces transcription of a variety of cytokines, chemokines, and growth factor, e.g., C-X-C motif ligand 1 (Cxcl1) and IL-6 [8,9,10]. Upon binding with the receptors, insulin (or IGF1) leads to autophosphorylation of the β subunit of IR or IGF1R [14], which in turn recruits insulin receptor substrates-1 (IRS-1)
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