PMID- 22363816 OWN - NLM STAT- MEDLINE DCOM- 20120629 LR - 20220331 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 7 IP - 2 DP - 2012 TI - Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PG - e32195 LID - 10.1371/journal.pone.0032195 [doi] LID - e32195 AB - BACKGROUND: Resveratrol have been known to possess many pharmacological properties including antioxidant, cardioprotective and anticancer effects. Although current studies indicate that resveratrol produces neuroprotection against neurological disorders, the precise mechanisms for its beneficial effects are still not fully understood. We investigate the effect of anti-inflammatory and mechamisms of resveratrol by using lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells. METHODOLOGY/PRINCIPAL FINDINGS: BV-2 cells were treated with resveratrol (25, 50, and 100 microM) and/or LPS (1 microg/ml). Nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess reagent and ELISA. The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by RT-PCR and double immunofluorescence labeling, respectively. Phosphorylation levels of PTEN (phosphatase and tensin homolog deleted on chromosome 10), Akt, mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) cascades, inhibitor kappaB-alpha (IkappaB-alpha) and cyclic AMP-responsive element-binding protein (CREB) were measured by western blot. Resveratrol significantly attenuated the LPS-induced expression of NO, PGE2, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and nuclear factor-kappaB (NF-kappaB) in BV-2 cells. Resveratrol increased PTEN, Akt and mTOR phosphorylation in a dose-dependent manner or a time-dependent manner. Rapamycin (10 nM), a specific mTOR inhibitor, blocked the effects of resveratrol on LPS-induced microglial activation. In addition, mTOR inhibition partially abolished the inhibitory effect of resveratrol on the phosphorylation of IkappaB-alpha, CREB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). CONCLUSION AND IMPLICATIONS: This study indicates that resveratrol inhibited LPS-induced proinflammatory enzymes and proinflammatory cytokines via down-regulation phosphorylation of NF-kappaB, CREB and MAPKs family in a mTOR-dependent manner. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of resveratrol. FAU - Zhong, Lian-Mei AU - Zhong LM AD - School of Life Science, Yunnan University, Kunming, Yunnan, China. FAU - Zong, Yi AU - Zong Y FAU - Sun, Lin AU - Sun L FAU - Guo, Jia-Zhi AU - Guo JZ FAU - Zhang, Wei AU - Zhang W FAU - He, Ying AU - He Y FAU - Song, Rui AU - Song R FAU - Wang, Wen-Min AU - Wang WM FAU - Xiao, Chun-Jie AU - Xiao CJ FAU - Lu, Di AU - Lu D LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120221 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Creb1 protein, mouse) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (I-kappa B Proteins) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (Nfkbia protein, mouse) RN - 0 (RNA, Messenger) RN - 0 (Stilbenes) RN - 0 (Tumor Necrosis Factor-alpha) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.99.- (Ptgs2 protein, mouse) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - K7Q1JQR04M (Dinoprostone) RN - Q369O8926L (Resveratrol) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Cell Survival/drug effects MH - Cells, Cultured MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Cyclooxygenase 2/genetics/metabolism MH - Cytoprotection/drug effects MH - Dinoprostone/metabolism MH - Gene Expression Regulation/drug effects MH - I-kappa B Proteins MH - Inflammation/enzymology/genetics/*pathology MH - Interleukin-1beta/genetics/metabolism MH - Lipopolysaccharides/*pharmacology MH - MAP Kinase Signaling System/drug effects MH - Mice MH - Microglia/drug effects/enzymology/*metabolism/pathology MH - NF-KappaB Inhibitor alpha MH - NF-kappa B/metabolism MH - Nitric Oxide/metabolism MH - Nitric Oxide Synthase Type II/genetics/metabolism MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA, Messenger/genetics/metabolism MH - Resveratrol MH - Signal Transduction/*drug effects MH - Sirolimus/pharmacology MH - Stilbenes/chemistry/*pharmacology MH - TOR Serine-Threonine Kinases/*metabolism MH - Tumor Necrosis Factor-alpha/genetics/metabolism PMC - PMC3283735 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2012/03/01 06:00 MHDA- 2012/06/30 06:00 PMCR- 2012/02/21 CRDT- 2012/02/25 06:00 PHST- 2011/10/10 00:00 [received] PHST- 2012/01/24 00:00 [accepted] PHST- 2012/02/25 06:00 [entrez] PHST- 2012/03/01 06:00 [pubmed] PHST- 2012/06/30 06:00 [medline] PHST- 2012/02/21 00:00 [pmc-release] AID - PONE-D-11-19897 [pii] AID - 10.1371/journal.pone.0032195 [doi] PST - ppublish SO - PLoS One. 2012;7(2):e32195. doi: 10.1371/journal.pone.0032195. Epub 2012 Feb 21.