Lobolide, a diterpene, blockades the NF-κB pathway and p38 and ERK MAPK activity in macrophages in vitro

Abstract

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.

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

“…The research from Ponnusamy et al points out that specific inhibition of the ERK pathway could block autophagy in the pathogenesis of renal fibroblasts 51. Furthermore, TAK1 is an important signalling pathway located upstream of p38 and ERK, which play critical roles in various types of physiological processes52, 53 . Kim SI showed that TGF‐β1 induced autophagy in mesangial cells via the TAK1‐MKK3‐p38 signalling pathway 54.…”

Anti-inflammatory effect of diterpenes-enriched fractions from Pterodon polygalaeflorus through inhibition of macrophage migration and cytokine production

“…Inhibition of the NF‐κB pathway can be considered as a possible mechanism for reducing cytokine expression and NO production, as previously described with LPS‐stimulated RAW 264.7 cells . The reduction in these cytokine levels in LPS‐stimulated macrophage, by Fr3 and Fr4, may also be related to inhibition of p38 MAPK as this kinase inhibition has been related to the inhibition mechanism of IL‐β 1 and TNF‐α production for the diterpene lobolide . On the other hand, dexamethasone suppresses the IL‐10 expression, both at the protein and at the mRNA level, as previously reported on LPS‐stimulated peripheral blood mononuclear cells …”

Activities and Molecular Mechanisms of Diterpenes, Diterpenoids, and Their Derivatives in Rheumatoid Arthritis

“…It significantly inhibited IL-1β-induced nuclear translocation of NF-κB-p65, suggesting that it is primarily regulated through the NF-κB signaling pathway. Lobolide, a cembrane diterpene, also acts through the NF-κB signaling pathway [116]. Moreover, andrographolide attenuated mouse cortical chemokine levels from the CC and CXC subfamilies in LPS-induced chemokine upregulation in a mouse model [117].…”