RESUMO
Mammalian target of rapamycin (mTOR), a serine/threonine kinase regulate variety of cellular functions including cell growth, differentiation, cell survival, metabolism, and stress response, is now appreciated to be a central regulator of immune responses. Because mTOR inhibitors enhanced the anti-inflammatory activities of regulatory T cells and decreased the production of proinflammatory cytokines by macrophages, mTOR has been a pharmacological target for inflammatory diseases. In this study, we examined the role of mTOR in the production of proinflammatory and vasodilator mediators in zymosan-induced non-septic shock model in rats. To elucidate the mechanism by which mTOR contributes to non-septic shock, we have examined the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system caused by mTOR/mitogen-activated protein kinase kinase (MEK1)/extracellular signal-regulated kinase (ERK1/2)/inhibitor κB kinase (IKKß)/inhibitor of κB (IκB-α)/nuclear factor-κB (NF-κB) signalling pathway activation. After 1 h of zymosan (500 mg/kg, i.p.) administration to rats, mean arterial blood pressure (MAP) was decreased and heart rate (HR) was increased. These changes were associated with increased expression and/or activities of ribosomal protein S6, MEK1, ERK1/2, IKKß, IκB-α and NF-κB p65, and NADPH oxidase system activity in cardiovascular and renal tissues. Rapamycin (1 mg/kg, i.p.), a selective mTOR inhibitor, reversed these zymosan-induced changes in these tissues. These observations suggest that activation of mTOR/MEK1/ERK1/2/IKKß/IκB-α/NF-κB signalling pathway with proinflammatory and vasodilator mediator formation and NADPH oxidase system activity contributes to systemic inflammation in zymosan-induced non-septic shock. Thus, mTOR may be an optimal target for the treatment of the diseases characterized by the severe systemic inflammatory response.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Proteínas I-kappa B/metabolismo , Inflamação/prevenção & controle , MAP Quinase Quinase 1/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Zimosan , Animais , Pressão Arterial/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/enzimologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Vasodilatação/efeitos dos fármacosRESUMO
Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic diseases, and inflammation. Although mTOR participates in Toll-like receptor 4 signalling in different cell types, the role of this enzyme in sepsis pathogenesis and its effects on hypotension and inflammation in endotoxemic rats remains unclear. In this study we investigated the effects of mTOR inhibition on lipopolysaccharide (LPS)-induced changes on expressions and/or activities of ribosomal protein S6 (rpS6), an mTOR substrate, nuclear factor-κB (NF-κB) p65, inhibitor κB (IκB)-α, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 with production of nitric oxide, peroxynitrite, prostacyclin, and tumor necrosis factor (TNF)-α and activity of myeloperoxidase (MPO), which results in hypotension and inflammation. Injection of LPS (10mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate that were associated with elevated nitrotyrosine, 6-keto-PGF1α, and TNF-α levels and MPO activity, and increased expressions and/or activities of rpS6, NF-κB p65, iNOS, and COX-2 and decreased expression of IκB-α in renal, cardiac, and vascular tissues. LPS also increased serum and tissue nitrite levels. Rapamycin (1mg/kg, i.p.) given one h after injection of LPS reversed these effects of LPS. These data suggest that the activation of mTOR/IκB-α/NF-κB pathway associated with vasodilator and proinflammatory mediator formation contributes to LPS-induced hypotension and inflammation.