PMID- 25022959 OWN - NLM STAT- MEDLINE DCOM- 20150910 LR - 20191210 IS - 1096-0023 (Electronic) IS - 1043-4666 (Linking) VI - 69 IP - 1 DP - 2014 Sep TI - Interleukin-18 directly protects cortical neurons by activating PI3K/AKT/NF-kappaB/CREB pathways. PG - 29-38 LID - S1043-4666(14)00118-5 [pii] LID - 10.1016/j.cyto.2014.05.003 [doi] AB - Interleukin-18 (IL-18), a member of the IL-1 family of cytokines, was initially identified as an interferon (IFN)-gamma-inducing factor. IL-18 is expressed in both immune and non-immune cells and participates in the adjustment of multitude cellular functions. Nonetheless, the effects of IL-18 on cortical neurons have not been explored. The present study was conducted to investigate the influence of IL-18 on rat primary cortical neurons and elucidate the underlying mechanisms. We proved that rrIL-18 increased the brain-derived neurotrophic factor (BDNF) expression in a time-dependent manner. Treatment with rrIL-18 (50 ng/ml) deactivated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by facilitating its phosphorylation, enhanced the expression of Phosphoinositide 3-OH kinase (PI3K) and p-Akt, standing for the activation of the PI3K/Akt pathway. As its pivotal downstream pathways, nuclear factor-kappa B (NF-kappaB), cAMP-responsive element binding protein (CREB)/Bcl-2 and glycogen synthase kinase-3beta (GSK-3beta) were examined in further steps. Our data revealed that rrIL-18 stimulated NF-kappaB activation, improved p-CREB and anti-apoptotic Bcl-2 expression levels. But rrIL-18 had little or no effect on GSK-3beta pathway. Besides, rrIL-18 increased levels of BDNF and Bcl-2/Bax ratio and decreased cleaved caspase-3 expression to protect cortical neurons from damage induced by oxygen-glucose deprivation (OGD). These results in vitro showed the protection of IL-18 on cortical neurons. And this direct neuroprotective effect of IL-18 is crippled by PI3K inhibitor wortmannin. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Zhou, Jia AU - Zhou J AD - Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China. FAU - Ping, Feng-feng AU - Ping FF AD - Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Department of Clinical Laboratory Science, Wuxi People's Hospital affiliated to Nanjing Medical University, China. FAU - Lv, Wen-ting AU - Lv WT AD - Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China. FAU - Feng, Jun-yi AU - Feng JY AD - Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China. FAU - Shang, Jing AU - Shang J AD - Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China. Electronic address: shangjing21cn@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140603 PL - England TA - Cytokine JT - Cytokine JID - 9005353 RN - 0 (Androstadienes) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Interleukin-18) RN - 0 (NF-kappa B) RN - 0 (Neuroprotective Agents) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (Pten protein, rat) RN - EC 3.4.22.- (Casp3 protein, rat) RN - EC 3.4.22.- (Caspase 3) RN - XVA4O219QW (Wortmannin) SB - IM MH - Androstadienes/pharmacology MH - Animals MH - Brain-Derived Neurotrophic Factor/biosynthesis MH - Caspase 3/biosynthesis MH - Cerebral Cortex/cytology/*metabolism MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Enzyme Activation/drug effects MH - Glycogen Synthase Kinase 3/biosynthesis/metabolism MH - Glycogen Synthase Kinase 3 beta MH - Interleukin-18/metabolism/*pharmacology MH - NF-kappa B/metabolism MH - Neurons/metabolism MH - Neuroprotective Agents/*pharmacology MH - PTEN Phosphohydrolase/metabolism MH - Phosphatidylinositol 3-Kinases/biosynthesis/*metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation MH - Protein Kinase Inhibitors/pharmacology MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Proto-Oncogene Proteins c-bcl-2/biosynthesis MH - Rats MH - Wortmannin OTO - NOTNLM OT - CREB OT - Cortical neurons OT - IL-18 OT - NF-kappaB OT - PI3K/Akt EDAT- 2014/07/16 06:00 MHDA- 2015/09/12 06:00 CRDT- 2014/07/16 06:00 PHST- 2014/01/13 00:00 [received] PHST- 2014/04/12 00:00 [revised] PHST- 2014/05/01 00:00 [accepted] PHST- 2014/07/16 06:00 [entrez] PHST- 2014/07/16 06:00 [pubmed] PHST- 2015/09/12 06:00 [medline] AID - S1043-4666(14)00118-5 [pii] AID - 10.1016/j.cyto.2014.05.003 [doi] PST - ppublish SO - Cytokine. 2014 Sep;69(1):29-38. doi: 10.1016/j.cyto.2014.05.003. Epub 2014 Jun 3.