title: Lobolide, a diterpene, blockades the NF-κB pathway and p38 and ERK MAPK activity in macrophages in vitro.
abstract: OBJECTIVE
  Recent studies have shown that constitutive activation of the nuclear factor κB (NF-κB) plays a key role in chronic inflammation and cancers. The aim of this study was to characterize lobolide, a cembrane diterpene, as a drug candidate targeting the NF-κB signaling pathway.
  
  
  METHODS
  A HEK 293/NF-κB-Luc stable cell line was constructed to evaluate the effect of lobolide on NF-κB activation. THP-1 human monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were tested. Lipopolysaccharide (LPS)-induced TNFα and IL-1β production and activation of the TAK1-IKK-NF-κB pathway were studied using ELISA and Western blot analysis.
  
  
  RESULTS
  In HEK 293/NF-κB-Luc stable cells, lobolide (0.19-50 μmol/L) inhibited NF-κB activation in a concentration-dependent manner with an IC(50) value of 4.2 ± 0.3 μmol/L. Treatment with lobolide (2.5-10 μmol/L) significantly suppressed LPS-induced production of TNFα and IL-1β in both THP-1 cells and PBMCs. In THP-1 cells, the suppression was partially caused by blockade of the translocation of NF-κB from the cytoplasm to the nucleus via affecting the TAK1-IKK-NF-κB pathway and p38 and ERK MAPK activity.
  
  
  CONCLUSIONS
  Lobolide is a potential inhibitor of the NF-κB pathway, which blocks the translocation of NF-κB from the cytoplasm to the nucleus. Lobolide inhibits LPS-stimulated TNFα and IL-1β release, suggesting that the compound might be an anti-inflammatory compound.
authors.affiliation: Glycochemistry and Glycobiology Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiao-fen
authors.initials: XF
authors.lastname: Lv
authors.forename: Si-han
authors.initials: SH
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Jian-ping
authors.initials: JP
authors.lastname: Fang
authors.forename: Yue-wei
authors.initials: YW
authors.lastname: Guo
authors.forename: Kan
authors.initials: K
authors.lastname: Ding
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D037421:Anthozoa / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008156:Luciferases / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D015394:Molecular Structure; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004224:Diterpenes; D051996:Transcription Factor RelA; C578670:lobolide; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases