Cadmium selectively induces MIP-2 and COX-2 through PTEN-mediated Akt activation in RAW264.7 cells.
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.
Department of Toxicology, Anhui Medical University, Hefei, China.
Yin-Yin
YY
Huang
Mi-Zhen
MZ
Xia
Hua
H
Wang
Xiao-Jing
XJ
Liu
Yong-Fang
YF
Hu
Yuan-Hua
YH
Chen
Cheng
C
Zhang
De-Xiang
DX
Xu
D000818:Animals; D019256:Cadmium Chloride / Q000633:toxicity*; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D054426:Chemokine CXCL2 / Q000096:biosynthesis* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism; D015151:Immunoblotting; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D004785:Environmental Pollutants; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005978:Glutathione; D019256:Cadmium Chloride
cadmium; inflammation; phosphatidylinositol 3-kinase (PI3K)/Akt; toxicity