Avaliação do efeito da metionina e/ou metionina sulfóxido sobre o fenótipo de macrófagos e marcadores de inflamação.

Abstract

The hypermethioninemia is an inborn error of metabolism (IEM), characterized by the deficiency of the enzyme methionine adenosyltransferase (MAT), which can result in high blood concentrations of methionine, and the presence of metabolites such as methionine sulfoxide, methanethiol and hydrogen sulfide in plasma and urine of patients affected by this disease. Therefore, hypermethioninemic patients may exhibit cerebral edema, psychomotor changes and liver disorders involving inflammation and oxidative stress, whose pathophysiology is not completely established. Data from literature suggest that a diet supplemented with methionine changes the pro-oxidant / antioxidant status of rat brain and liver. Macrophages when activated in response to recognition of danger signals such as microbial products, cytokines and mediators extravasated by damaged cells, such as ATP (adenosine triphosphate), present increased ability to release pro-inflammatory and cytotoxic mediators as reactive oxygen species (ROS), reactive nitrogen species (RNS), hydrolytic enzymes, bioactive lipids and cytokines. Thus, this study aimed to investigate the in vitro effect of methionine and/or methionine sulfoxide on the phenotype expressed by mouse macrophages and evaluate some inflammatory parameters associated with oxidative stress and ectonucleotidase activity of these cells. Our results showed that exposure of macrophages at high methionine and / or methionine sulfoxide concentration induced M1/classical macrophage polarization, which is related to a proinflammatory response characterized by increased iNOS (Nitric oxide synthase induced) activity and release of TNF-α (Tumor Necrosis Factor-alpha). In addition, treatment with methionine (1 mM) and/or methionine sulfoxide (0.5 mM) modulated differentially the activity of the antioxidant enzymes SOD (superoxide dismutase) and CAT (catalase) in cultured macrophages. However, significant differences of the antioxidant enzyme GPx (glutathione peroxidase) activity were not observed. Regarding the ectonucleotidases, our results showed that the treatment with methionine sulfoxide alone or in combination with methionine increased the ATPase/ADPase activities in macrophages. Together, our findings suggest that the treatment with methionine and/or methionine sulfoxide induced M1/classical macrophage polarization and modulated antioxidant enzyme activities as well as of ectonucleotidases which may be involved in the pathophysiology of diseases, thus contributing to the activation of the inflammatory/immune system in hypermethioninemic patients