title: Ketamine reduces LPS-induced HMGB1 via activation of the Nrf2/HO-1 pathway and NF-κB suppression.
abstract: BACKGROUND
  Ketamine, as an anesthetic agent, has an anti-inflammatory effect. In the present study, we investigated whether ketamine inhibits release of high mobility group box 1 (HMGB1), a late-phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated macrophages through heme oxygenase-1 (HO-1) induction.
  
  
  METHODS
  Macrophages were preincubated with various concentrations of ketamine and then treated with LPS (1 μg/mL). The cell culture supernatants were collected to measure inflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor-α, and interleukin 1β) by enzyme-linked immunosorbent assay. Moreover, HO-1 protein expression, the phosphorylation and degradation of IκB-α, and the nuclear translocation of nuclear factor E2-related factor 2 and nuclear factor κB (NF-κB) p65 were tested by Western blot analysis. In addition, to further identify the role of HO-1 in this process, tin protoporphyrin (SnPP), an HO-1 inhibitor, was used.
  
  
  RESULTS
  Ketamine treatment dose-dependently attenuated the increased levels of proinflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor α, and interleukin 1β) and increased the HO-1 protein expression in LPS-activated macrophages. Furthermore, ketamine suppressed the phosphorylation and degradation of IκB-α as well as the LPS-stimulated nuclear translocation of NF-κB p65 in macrophages. In addition, the present study also demonstrated that ketamine induced HO-1 expression through the nuclear translocation of nuclear factor E2-related factor 2 in macrophages. The effects of ketamine on LPS-induced proinflammatory cytokines production were partially reversed by the HO inhibitor tin protoporphyrin (SnPP).
  
  
  CONCLUSIONS
  Ketamine inhibits the release of HMGB1 in LPS-stimulated macrophages, and this effect is at least partly mediated by the activation of the Nrf2/HO-1 pathway and NF-κB suppression.
authors: From the Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors: Yonghong
authors: Y
authors: Tan
authors: Qiong
authors: Q
authors: Wang
authors: Yingjun
authors: Y
authors: She
authors: Xiaobao
authors: X
authors: Bi
authors: Baisong
authors: B
authors: Zhao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology; D010766:Phosphorylation; D011524:Protoporphyrins / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D011524:Protoporphyrins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007649:Ketamine; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1