Cadmium selectively induces MIP-2 and COX-2 through PTEN-mediated Akt activation in RAW264.7 cells

• Published in: Toxicological sciences Vol. 138; no. 2; pp. 310 - 321
• Main Authors: Huang, Yin-Yin, Xia, Mi-Zhen, Wang, Hua, Liu, Xiao-Jing, Hu, Yong-Fang, Chen, Yuan-Hua, Zhang, Cheng, Xu, De-Xiang
• Format: Journal Article
• Language: English
• Published: United States 01.04.2014
• Subjects: Animals; Cadmium Chloride - toxicity; Cell Culture Techniques; Cell Line; Cell Survival - drug effects; Chemokine CXCL2 - biosynthesis; Chemokine CXCL2 - genetics; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - genetics; Dose-Response Relationship, Drug; Environmental Pollutants - toxicity; Enzyme Induction; Glutathione - metabolism; Immunoblotting; Macrophages - drug effects; Macrophages - enzymology; Macrophages - metabolism; Mice; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; Time Factors; Up-Regulation; toxicity; cadmium; phosphatidylinositol 3-kinase (PI3K)/Akt; inflammation
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfu013

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.