7b, a novel naphthalimide derivative, exhibited anti-inflammatory effects via targeted-inhibiting TAK1 following down-regulation of ERK1/2- and p38 MAPK-mediated activation of NF-κB in LPS-stimulated RAW264.7 macrophages.
Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as cancers. 7b, a novel naphthalimide-based DNA intercalator, has exhibited anti-inflammatory effects in phorbol12-myristate 13-acetate/phytohemagglutinin (PMA/PHA)-induced inflammatory responses of Jurkat T cells in our previous study. Here, we tried to further investigate its anti-inflammatory potential and the possible underlying mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and primary mouse macrophages. In our current study, ELISA and Real-time PCR revealed that non-toxic doses of 7b reduced the production and expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in LPS-induced RAW264.7 cells and primary mouse macrophages. Moreover, 7b dose-dependently suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO). Except for COX-1, non-toxic doses of 7b exhibited parallel inhibition of LPS-induced expression of COX-2 and iNOS at both mRNA and protein levels. The molecular mechanism was associated with inhibition of the phosphorylation/degradation of IκB-α and nuclear translocation of the NF-κB p65. Further analysis of upstream mechanisms showed that blocking of NF-κB activation by 7b was mediated by inhibiting TAK1-downstream extracellular signal-regulated kinase (ERK1/2) and p38 kinase signal pathway. Taken together, these results indicated that 7b exhibited anti-inflammatory effects by targeting inhibiting TAK1, leading to ERK1/2- and p38 MAPK-mediated inactivation of NF-κB in LPS-stimulated RAW264.7 cells, and this would make 7b a strong candidate for further study as anti-inflammatory agent.
['Shao|Jin|J|', 'Li|Yiquan|Y|', 'Wang|Ziyuan|Z|', 'Xiao|Mengmeng|M|', 'Yin|Peihao|P|', 'Lu|Yanhua|Y|', 'Qian|Xuhong|X|', 'Xu|Yufang|Y|', 'Liu|Jianwen|J|']
D000818:Animals D000894:Anti-Inflammatory Agents, Non-Steroidal D002460:Cell Line D051546:Cyclooxygenase 2 D015232:Dinoprostone D015536:Down-Regulation D008070:Lipopolysaccharides D020930:MAP Kinase Kinase Kinases D020935:MAP Kinase Signaling System D017737:Macrophages, Peritoneal D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D058990:Molecular Targeted Therapy D016328:NF-kappa B D053644:Naphthalimides D009569:Nitric Oxide D052247:Nitric Oxide Synthase Type II D010879:Piperazines D015533:Transcriptional Activation D048051:p38 Mitogen-Activated Protein Kinases
7b Anti-inflammatory TAK1 NF-κB MAPK