title: The effect of bortezomib on expression of inflammatory cytokines and survival in a murine sepsis model induced by cecal ligation and puncture.
abstract: OBJECTIVE
  Although the proteasome inhibitor known as bortezomib can modulate the inflammatory process through the nuclear factor-kappa B signaling pathway, the immunomodulatory effect of pre-incubated bortezomib has not been fully evaluated for inflammation by infectious agents. Therefore, we evaluated the effect of bortezomib on the expression of inflammatory cytokines and mediators in macrophage cell lines and on survival in a murine peritonitis sepsis model.
  
  
  METHODS
  Bortezomib was applied 1 hr before lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. The cecal ligation and puncture (CLP) experiments were performed in C57BL/6J mice.
  
  
  RESULTS
  Pre-incubation with bortezomib (25 nM or 50 nM) prior to LPS (50 ng/mL or 100 ng/mL) stimulation significantly recovered the number of viable RAW 264.7 cells compared to those samples without pre-incubation. Bortezomib decreased various inflammatory cytokines as well as nitric oxide production in LPS-stimulated cells. The 7-day survival rate in mice that had received bortezomib at 0.01 mg/kg concentration 1 hr prior to CLP was significantly higher than in the mice that had only received a normal saline solution of 1 mL 1 hr prior to CLP. In addition, the administration of bortezomib at 0.01 mg/kg concentration 1 hr before CLP resulted in a significant decrease in inflammation of the lung parenchyma. Collectively, pretreatment with bortezomib showed an increase in the survival rate and changes in the levels of inflammatory mediators.
  
  
  CONCLUSIONS
  These results support the possibility of pretreatment with bortezomib as a new therapeutic target for the treatment of overwhelming inflammation, which is a characteristic of severe sepsis.
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Woo
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Jeong
authors.affiliation: Department of Microbiology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jeon Soo
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Brain Korea 21 Project for Medical Science, Brain Research Institute and Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. jmkim@yuhs.ac.
authors.forename: June Myung
authors.initials: JM
authors.lastname: Kim
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002432:Cecum / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002918:Chymotrypsin / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism*; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011677:Punctures; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy*
chemical_list: D001897:Boronic Acids; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D009569:Nitric Oxide; D000069286:Bortezomib; D002918:Chymotrypsin
keywords: Bortezomib; cecal ligation and puncture; inflammatory cytokines; lipopolysaccharide; proteasome inhibitor