Protection by mTOR Inhibition on Zymosan-Induced Systemic Inflammatory Response and Oxidative/Nitrosative Stress: Contri
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ORIGINAL ARTICLE
Protection by mTOR Inhibition on Zymosan-Induced Systemic Inflammatory Response and Oxidative/Nitrosative Stress: Contribution of mTOR/MEK1/ERK1/2/IKKβ/IκB-α/NF-κB Signalling Pathway Seyhan Sahan-Firat,1,3 Meryem Temiz-Resitoglu,1 Demet Sinem Guden,1 Sefika Pinar Kucukkavruk,1 Bahar Tunctan,1 Ayse Nihal Sari,1 Zumrut Kocak,1 and Kafait U. Malik2
Abstract— 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 zymosaninduced 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 (IKKβ)/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, IKKβ, 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/IKKβ/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. KEY WORDS: mTOR; zymosan; non-septic shock; systemic inflammatory response; rat. 1
Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169 Mersin, Turkey 2 Department of Pharmacology, College of Medicine, University of Tennessee, Center for Health Sciences, Memphis, TN, USA 3 To whom correspondence should be addressed at Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169 Mersin, Turkey. E-mail: [email protected]
INTRODUCTION Systemic inflammatory response syndrome (SIRS), actually having pro- and anti-inflammatory components, is an Binflammatory^ response against infectious or non-
0360-3997/17/0000-0001/0 # 2017 Springer Science+Business Media, LLC
Sahan-Firat, Temiz-Resitoglu, Guden, Kucukkavruk,
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