title: Phosphoinositide 3-kinase/Akt pathway is involved in mediating the anti-inflammation effects of magnesium sulfate.
abstract: BACKGROUND
  We sought to elucidate whether enhancing phosphoinositide 3-kinase (PI3K)/Akt activity is a crucial mechanism underlying the anti-inflammation effects of magnesium sulfate (MgSO4).
  
  
  METHODS
  Murine macrophages (RAW264.7 cells) were stimulated with endotoxin, endotoxin plus MgSO4, or endotoxin plus MgSO4 plus PI3K inhibitor (LY294002 or wortmannin). Control groups were run simultaneously. After harvesting, we assayed the expression of inflammatory mediators, transcriptional factor nuclear factor κB (NF-κB), and Akt.
  
  
  RESULTS
  MgSO4 significantly attenuated endotoxin-induced upregulation of inflammatory mediators and NF-κB, as macrophages treated with endotoxin plus MgSO4 had significantly lower tumor necrosis factor α (P = 0.022), macrophage inflammatory protein 2 (P = 0.040), phosphorylated (p)-NF-κB p65 (P = 0.003) and p-inhibitor-κB (P < 0.001) concentrations as well as lower NF-κB DNA binding (P = 0.001) than macrophages treated with endotoxin alone. Moreover, macrophages treated with endotoxin plus MgSO4 plus LY294002 or wortmannin had significantly higher tumor necrosis factor α (P = 0.013 and P < 0.001), macrophage inflammatory protein 2 (P = 0.023 and P = 0.003), p-NF-κB p65 (P = 0.006 and P < 0.001), and p-inhibitor-κB (P = 0.001 and P < 0.001) concentrations, as well as higher NF-κB DNA binding (P = 0.038 and P = 0.009), than macrophages treated with endotoxin plus MgSO4, suggesting that PI3K inhibitors reversed these effects of MgSO4. In contrast, macrophages treated with endotoxin plus MgSO4 had significantly higher p-Akt concentration than macrophages treated with endotoxin alone (P = 0.004). Moreover, macrophages treated with endotoxin plus MgSO4 also had significantly higher p-Akt concentration than macrophages treated with endotoxin plus MgSO4 plus LY294002 or wortmannin (P = 0.004 and P < 0.001).
  
  
  CONCLUSIONS
  Enhancing PI3K/Akt activity is a crucial mechanism underlying the anti-inflammation effects of MgSO4.
authors.affiliation: Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Nuan-Yen
authors.initials: NY
authors.lastname: Su
authors.forename: Tsui-Chin
authors.initials: TC
authors.lastname: Peng
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Tsai
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Huang
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008278:Magnesium Sulfate / Q000494:pharmacology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D002867:Chromones; D004731:Endotoxins; D004791:Enzyme Inhibitors; D008278:Magnesium Sulfate; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C514862:Akt1 protein, mouse
keywords: Chemokine; Cytokine; Endotoxin; Macrophages; MgSO(4); NF-κB