title: Interleukin-18 directly protects cortical neurons by activating PI3K/AKT/NF-κB/CREB pathways.
abstract: Interleukin-18 (IL-18), a member of the IL-1 family of cytokines, was initially identified as an interferon (IFN)-γ-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-κB), cAMP-responsive element binding protein (CREB)/Bcl-2 and glycogen synthase kinase-3β (GSK-3β) were examined in further steps. Our data revealed that rrIL-18 stimulated NF-κB activation, improved p-CREB and anti-apoptotic Bcl-2 expression levels. But rrIL-18 had little or no effect on GSK-3β 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.
authors.affiliation: Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Feng-feng
authors.initials: FF
authors.lastname: Ping
authors.affiliation: Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China.
authors.forename: Wen-ting
authors.initials: WT
authors.lastname: Lv
authors.affiliation: Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, China.
authors.forename: Jun-yi
authors.initials: JY
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Shang
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D053148:Caspase 3 / Q000096:biosynthesis; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020382:Interleukin-18 / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D019208:Brain-Derived Neurotrophic Factor; D053148:Caspase 3; D017362:Cyclic AMP Response Element-Binding Protein; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D020382:Interleukin-18; D016328:NF-kappa B; D018696:Neuroprotective Agents; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D000077191:Wortmannin; C000605508:Gsk3b protein, rat; C487216:Pten protein, rat; C505410:Casp3 protein, rat
keywords: CREB; Cortical neurons; IL-18; NF-κB; PI3K/Akt