tailieunhanh - Báo cáo khoa học: Muramyl-dipeptide-induced mitochondrial proton leak in macrophages is associated with upregulation of uncoupling protein 2 and the production of reactive oxygen and reactive nitrogen species

The synthetic immunomodulator muramyl dipeptide (MDP) has been shown to induce, in vivo, mitochondrial proton leak. In the present work, we extended these findings to the cellular level and confirmed the effects of MDPin vitro on murine macrophages. | IFEBS Journal Muramyl-dipeptide-induced mitochondrial proton leak in macrophages is associated with upregulation of uncoupling protein 2 and the production of reactive oxygen and reactive nitrogen species Takla G. El-Khoury Georges M. Bahr and Karim S. Echtay Faculty of Medicine and MedicalSciences and Faculty of Sciences University of Balamand Tripoli Lebanon Keywords mitochondria muramylpeptides nitric oxide respiratory control ratio superoxide anion UCP2 Correspondence K. S. Echtay Faculty of Medicine and MedicalSciences University of Balamand PO Box 100 Tripoli Lebanon Fax 961 6 930279 Tel 961 3 714125 E-mail Received 5 May 2011 revised 13 June 2011 accepted 28 June 2011 doi The synthetic immunomodulator muramyl dipeptide MDP has been shown to induce in vivo mitochondrial proton leak. In the present work we extended these findings to the cellular level and confirmed the effects of MDP in vitro on murine macrophages. The macrophage system was then used to analyse the mechanism of the MDP-induced mitochondrial proton leak. Our results demonstrate that the cellular levels of superoxide anion and nitric oxide were significantly elevated in response to MDP. Moreover isolated mitochondria from cells treated with MDP presented a significant decrease in respiratory control ratio an effect that was absent following treatment with a non-toxic analogue such as murabutide. Stimulation of cells with MDP but not with murabutide rapidly upregulates the expression of the mitochondrial protein uncoupling protein 2 UCP2 and pretreatment with vitamin E attenuates upregulation of UCP2. These findings suggest that the MDP-induced reactive species upregulate UCP2 expression in order to counteract the effects of MDP on mitochondrial respiratory efficiency. Introduction Uncoupling proteins UCPs are members of the anion carrier family molecules present in the inner mitochondrial membrane. Mammals express five UCP homologues

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