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

Autor: Zumrut Kocak, Bahar Tunctan, Demet Sinem Guden, Sefika Pinar Kucukkavruk, Ayse Nihal Sari, Kafait U. Malik, Seyhan Sahan-Firat, Meryem Temiz-Resitoglu
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Time Factors
Immunology
Anti-Inflammatory Agents
MAP Kinase Kinase 1
Nitric Oxide Synthase Type II
Inflammation
Pharmacology
Antioxidants
Proinflammatory cytokine
03 medical and health sciences
NF-KappaB Inhibitor alpha
medicine
Immunology and Allergy
Animals
Arterial Pressure
Phosphorylation
Rats
Wistar
Protein kinase A
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Mitogen-Activated Protein Kinase 1
Sirolimus
NADPH oxidase
Mitogen-Activated Protein Kinase 3
biology
Chemistry
Kinase
TOR Serine-Threonine Kinases
NF-kappa B
Zymosan
Vasodilation
Disease Models
Animal
Oxidative Stress
030104 developmental biology
Cyclooxygenase 2
Nitrosative Stress
biology.protein
Cytokines
I-kappa B Proteins
medicine.symptom
Signal transduction
Inflammation Mediators
medicine.drug
Signal Transduction
Zdroj: Inflammation. 41(1)
ISSN: 1573-2576
Popis: 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.
Databáze: OpenAIRE
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