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KMID : 0358520090210030259
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Korean Journal of Occupational and Environmental Medicine
2009 Volume.21 No. 3 p.259 ~ p.266
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Induction of Inducible Nitric Oxide Synthase Expression by Manganese in C6 Glioma Cells
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Yu Gyeong-Im
Chung In-Sung
Lee Mi-Young
Shin Dong-Hoon
Lee Dong-Hyul
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Abstract
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Objective: It is well established that manganese neurotoxicity is associated with clinical symptoms similar to those of idiopathic Parkinson’s disease. Recent research has shown that the exposure to manganese(MnCl2) leads to induction of iNOS in BV2 microglial cells via iNOS transcriptional up-regulation and activation of both MAPKs and PI3K/Akt signaling pathways. Here, we further investigated the effect and the action mechanism of MnCl2 on iNOS expression in C6 glioma cells.
Methods: Western blot analyses demonstrated that treatment with MnCl2 at 250 μM was sufficient to induce iNOS at both the protein and mRNA levels in C6 cells.
Results: These studies demonstrated that the induction of iNOS protein and mRNA was visible after 4 h- and 2 h-treatment with MnCl2, respectively. MnCl2 treatment led to strong phosphorylation of JNKs and ERKs, members of MAP kinases (MAPKs), and Akt, a PI3-kinase (PI3K) downstream effector, in C6 cells. MnCl2 treatment had no effect on IκB-αin C6 cells. Notably, pretreatment with LY294002 (a PI3K inhibitor), which inhibited phosphorylation of Akt by MnCl2, caused strong suppression of MnCl2-induced iNOS protein and mRNA expression in C6 cells. Moreover, pretreatment with SP600125 (an inhibitor of JNKs) and PD98050 (an inhibitor of ERKs), which respectively interfered with MnCl2-mediated phosphorylation of JNKs and ERKs, led to the partial suppression of MnCl2-induced iNOS protein. Interestingly, pretreatment with LY294002 inhibited phosphorylation of not only Akt, but also ERKs and JNKs, in response to MnCl2. Moreover, there was an effective suppression of MnCl2-mediated phosphorylation of AKT by SP600125.
Conclusion: These results collectively suggest that MnCl2 induces iNOS expression in C6 glioma cells via activation of PI3K/Akt and JNK-ERK MAPK signaling proteins, whose activations seem to be mutually interconnected in response to MnCl2.
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KEYWORD
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Manganese, Inducible nitric oxide synthase, C6 glioma cells
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