AIM: 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. CONCLUSION: 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.
AIM: 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-1human 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 ERKMAPK activity. CONCLUSION: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: Wayne A Ray; C Michael Stein; James R Daugherty; Kathi Hall; Patrick G Arbogast; Marie R Griffin Journal: Lancet Date: 2002-10-05 Impact factor: 79.321
Authors: Koichi Kobayashi; Lorraine D Hernandez; Jorge E Galán; Charles A Janeway; Ruslan Medzhitov; Richard A Flavell Journal: Cell Date: 2002-07-26 Impact factor: 41.582
Authors: J R Kiefer; J L Pawlitz; K T Moreland; R A Stegeman; W F Hood; J K Gierse; A M Stevens; D C Goodwin; S W Rowlinson; L J Marnett; W C Stallings; R G Kurumbail Journal: Nature Date: 2000-05-04 Impact factor: 49.962