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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

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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 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 (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.

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Funding

This study was supported by the Research Fundation of Mersin University in Turkey with Project Number “2016-2-AP3-1490.”

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey

    Seyhan Sahan-Firat, Meryem Temiz-Resitoglu, Demet Sinem Guden, Sefika Pinar Kucukkavruk, Bahar Tunctan, Ayse Nihal Sari & Zumrut Kocak

  2. Department of Pharmacology, College of Medicine, University of Tennessee, Center for Health Sciences, Memphis, TN, USA

    Kafait U. Malik

Authors
  1. Seyhan Sahan-Firat
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  2. Meryem Temiz-Resitoglu
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  3. Demet Sinem Guden
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  4. Sefika Pinar Kucukkavruk
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  5. Bahar Tunctan
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  6. Ayse Nihal Sari
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  8. Kafait U. Malik
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Corresponding author

Correspondence to Seyhan Sahan-Firat.

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All animal experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The study protocols were approved by the Ethics Committee of Mersin University School of Medicine.

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The authors declare that they have no conflicts of interest.

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Sahan-Firat, S., Temiz-Resitoglu, M., Guden, D.S. et al. 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. Inflammation 41, 276–298 (2018). https://doi.org/10.1007/s10753-017-0686-2

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