title: Anti-inflammation effects of naloxone involve phosphoinositide 3-kinase delta and gamma.
abstract: BACKGROUND
  Phosphoinositide 3-kinase (PI3K) delta and gamma (the p110δ and p110γ isoforms of PI3K) actively participate in the process of inflammation. We sought to elucidate the possible roles of PI3Kδ and PI3Kγ in mediating the anti-inflammation effects of naloxone.
  
  
  METHODS
  Murine macrophages were treated with endotoxin, endotoxin plus naloxone, or endotoxin plus naloxone plus the PI3K inhibitors (the PI3Kδ inhibitor IC87114, the PI3Kγ inhibitor AS252424, or IC87114 plus AS252424) and denoted as the LPS, LPS + N, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS group, respectively. Differences in inflammatory molecules and levels of nuclear factor-κB (NF-κB) activation and Akt activation (indicator of PI3K activity) among these groups were compared.
  
  
  RESULTS
  The concentrations of inflammatory molecules (macrophage inflammatory protein 2, tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2/prostaglandin E2) and the levels of NF-κB activation (p-NF-κB p65 and p-inhibitor-κB concentrations and NF-κB-DNA binding activity) of the LPS + N group were significantly lower than those of the LPS group (all P < 0.001). These data confirmed the anti-inflammation effects of naloxone. Moreover, the anti-inflammation effects of naloxone could be counteracted by the inhibitors of PI3Kδ and PI3Kγ, as the concentrations of inflammatory molecules and the levels of NF-κB activation of the LPS + N group were significantly lower than those of the LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). In contrast, the concentration of phosphorylated Akt of the LPS + N group was significantly higher than those of the LPS, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05).
  
  
  CONCLUSIONS
  PI3Kδ and PI3Kγ play crucial roles in mediating the anti-inflammation effects of naloxone.
authors.affiliation: Department of Pathology, Mackay Medical College and Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
authors.forename: Tao-Yeuan
authors.initials: TY
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Nuan-Yen
authors.initials: NY
authors.lastname: Su
authors.affiliation: Department of Anesthesiology, Taipei Tzu Chi Hospital, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ping-Cheng
authors.initials: PC
authors.lastname: Shih
authors.affiliation: Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Tsai
authors.affiliation: Department of Anesthesiology, Taipei Tzu Chi Hospital, Taipei, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan. Electronic address: huangcj1112@gmail.com.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Huang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D019446:Endotoxemia / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016328:NF-kappa B; D009270:Naloxone; D009292:Narcotic Antagonists; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C421683:Pik3cd protein, mouse
keywords: Chemokine; Cytokine; Endotoxin; Macrophages; NF-κB; Naloxone