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- Title
Cadmium Selectively Induces MIP-2 and COX-2 Through PTEN-Mediated Akt Activation in RAW264.7 Cells.
- Authors
Huang, Yin-Yin; Xia, Mi-Zhen; Wang, Hua; Liu, Xiao-Jing; Hu, Yong-Fang; Chen, Yuan-Hua; Zhang, Cheng; Xu, De-Xiang
- Abstract
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 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.
- Subjects
CYCLOOXYGENASE 2; PHYSIOLOGICAL effects of cadmium; MACROPHAGE inflammatory proteins; PTEN protein; PHOSPHATIDYLINOSITOL 3-kinases; PHOSPHORYLATION
- Publication
Toxicological Sciences, 2014, Vol 138, Issue 2, p310
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfu013