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Increasing evidence demonstrates that cadmium(Cd)induces inflammation,but its mechanisms remain obscure.The present study showed that treatment with CdCl2 selectively upregulates macrophage inflammatory protein(MIP)-2 and cyclooxygenase(COX)-2 in RAW264.7 cells.Concomitantly,Cd2+ markedly elevated the level of phosphorylated Akt in dose-and time-dependent manners.LY294002,a specific inhibitor of phosphatidylinositol 3-kinase(PI3K),blocked Cd2+-evoked Akt phosphorylation.Correspondingly,LY294002 significantly repressed Cd2+-induced upregulation of MIP-2 and COX-2 in RAW264.7 cells.Further experiments showed that treatment with Cd2+ significantly reduced the level of PTEN protein in RAW264.7 cells.MG132,a specific proteasome inhibitor,blocked Cd2+-induced reduction in PTEN protein as well as Akt phosphorylation,implicating the involvement of proteasome-mediated PTEN degradation.Of interest,Cd2+-induced degradation of PTEN protein appears to be associated with PTEN ubiquitination.N-acetylcysteine,a glutathione(GSH)precursor,blocked Cd2+-evoked PTEN degradation as well as Akt phosphorylation.By contrast,L-buthionine-S,R-sulfoximine,an inhibitor of cellular GSH synthesis,exacerbated Cd2+-induced PTEN degradation and Akt phosphorylation.Alpha-phenyl-N-tert-butylnitrone(PBN)and vitamin C,two antioxidants,did not prevent from Cd2+-induced PTEN degradation and Akt phosphorylation.In conclusion,Cd2+ selectively induces MIP-2 and COX-2 through PTEN-mediated PI3K/Akt activation.Cellular GSH depletion mediates Cd2+-induced PTEN degradation and subsequent PI3K/Akt activation in macrophages.