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Int Immunopharmacol. 2013 Oct;17(2):216-28. doi: 10.1016/j.intimp.2013.06.008. Epub 2013 Jun 26.

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.

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  • 1School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China.

Abstract

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.

Copyright © 2013 Elsevier B.V. All rights reserved.

KEYWORDS:

7b; Anti-inflammatory; MAPK; NF-κB; TAK1

PMID:
23810444
[PubMed - indexed for MEDLINE]
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