PMID- 29110153 OWN - NLM STAT- MEDLINE DCOM- 20180924 LR - 20211204 IS - 1573-2576 (Electronic) IS - 0360-3997 (Linking) VI - 41 IP - 1 DP - 2018 Feb TI - Protection by mTOR Inhibition on Zymosan-Induced Systemic Inflammatory Response and Oxidative/Nitrosative Stress: Contribution of mTOR/MEK1/ERK1/2/IKKbeta/IkappaB-alpha/NF-kappaB Signalling Pathway. PG - 276-298 LID - 10.1007/s10753-017-0686-2 [doi] AB - 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 kappaB kinase (IKKbeta)/inhibitor of kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB) 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, IKKbeta, IkappaB-alpha and NF-kappaB 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/IKKbeta/IkappaB-alpha/NF-kappaB 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. FAU - Sahan-Firat, Seyhan AU - Sahan-Firat S AD - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey. seyhansahan06@gmail.com. FAU - Temiz-Resitoglu, Meryem AU - Temiz-Resitoglu M AD - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey. FAU - Guden, Demet Sinem AU - Guden DS AD - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey. FAU - Kucukkavruk, Sefika Pinar AU - Kucukkavruk SP AD - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey. FAU - Tunctan, Bahar AU - Tunctan B AD - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey. FAU - Sari, Ayse Nihal AU - Sari AN AD - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey. FAU - Kocak, Zumrut AU - Kocak Z AD - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, 33169, Mersin, Turkey. FAU - Malik, Kafait U AU - Malik KU AD - Department of Pharmacology, College of Medicine, University of Tennessee, Center for Health Sciences, Memphis, TN, USA. LA - eng GR - 2016-2-AP3-1490/Research Fundation of Mersin University/ PT - Journal Article PL - United States TA - Inflammation JT - Inflammation JID - 7600105 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antioxidants) RN - 0 (Cytokines) RN - 0 (I kappa B beta protein) RN - 0 (I-kappa B Proteins) RN - 0 (Inflammation Mediators) RN - 0 (NF-kappa B) RN - 0 (Nfkbia protein, rat) RN - 0 (Protein Kinase Inhibitors) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - 9010-72-4 (Zymosan) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, rat) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 1.14.99.1 (Ptgs2 protein, rat) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Mapk1 protein, rat) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Antioxidants/*pharmacology MH - Arterial Pressure/drug effects MH - Cyclooxygenase 2/metabolism MH - Cytokines/metabolism MH - Disease Models, Animal MH - I-kappa B Proteins/*metabolism MH - Inflammation/chemically induced/enzymology/physiopathology/*prevention & control MH - Inflammation Mediators/metabolism MH - MAP Kinase Kinase 1/*metabolism MH - Male MH - Mitogen-Activated Protein Kinase 1/*metabolism MH - Mitogen-Activated Protein Kinase 3/*metabolism MH - NF-KappaB Inhibitor alpha/*metabolism MH - NF-kappa B/*metabolism MH - Nitric Oxide Synthase Type II/metabolism MH - Nitrosative Stress/*drug effects MH - Oxidative Stress/*drug effects MH - Phosphorylation MH - Protein Kinase Inhibitors/*pharmacology MH - Rats, Wistar MH - Signal Transduction/drug effects MH - Sirolimus/*pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Time Factors MH - Vasodilation/drug effects MH - *Zymosan OTO - NOTNLM OT - mTOR OT - non-septic shock OT - rat OT - systemic inflammatory response OT - zymosan EDAT- 2017/11/08 06:00 MHDA- 2018/09/25 06:00 CRDT- 2017/11/08 06:00 PHST- 2017/11/08 06:00 [pubmed] PHST- 2018/09/25 06:00 [medline] PHST- 2017/11/08 06:00 [entrez] AID - 10.1007/s10753-017-0686-2 [pii] AID - 10.1007/s10753-017-0686-2 [doi] PST - ppublish SO - Inflammation. 2018 Feb;41(1):276-298. doi: 10.1007/s10753-017-0686-2.