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Chem Biol Interact. 2016 Jan 25;244:16-26. doi: 10.1016/j.cbi.2015.11.024. Epub 2015 Nov 24.

Inhibitory effects of alternaramide on inflammatory mediator expression through TLR4-MyD88-mediated inhibition of NF-кB and MAPK pathway signaling in lipopolysaccharide-stimulated RAW264.7 and BV2 cells.

Author information

1
College of Pharmacy, Wonkwang University, Iksan 570-749, Republic of Korea.
2
College of Medical and Life Sciences, Silla University, Busan 617-736, Republic of Korea.
3
Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongwon, Republic of Korea.
4
Hanbang Body-Fluid Research Center, Wonkwang University, Iksan 570-749, Republic of Korea.
5
College of Pharmacy, Wonkwang University, Iksan 570-749, Republic of Korea. Electronic address: yckim@wku.ac.kr.
6
College of Pharmacy, Wonkwang University, Iksan 570-749, Republic of Korea. Electronic address: hoh@wku.ac.kr.

Abstract

Alternaramide (1), a novel lipophilic depsipeptide, has been isolated from the extract of the marine-derived fungus Alternaria sp. SF-5016. In the course of extensive biological evaluation of 1, its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells were observed. In our initial study of the anti-inflammatory effects of 1, the compound suppressed production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated RAW264.7 and BV2 cells. Suppression of NO and PGE2 production was correlated with the inhibitory effect of 1 on expression of LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level in RAW264.7 and BV2 cells. In addition, 1 reduced production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-12 in LPS-stimulated RAW264.7 and BV2 cells. In the evaluation of the molecular mechanisms underlying the anti-inflammatory effects of 1, the compound was found to suppress the nuclear factor-kappa B (NF-κB) signaling pathway in RAW264.7 and BV2 cells stimulated with LPS. This suppression was mediated by disruption of phosphorylation and degradation of IκBα, an inhibitor of NF-κB, in the cytoplasm, and blocking of nuclear translocation of the NF-κB p50-p65 heterodimer. Furthermore, 1 inhibited phosphorylation of c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (MAPK), demonstrating its capacity to inhibit MAPK signaling. Finally, 1 markedly reduced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) at the mRNA and protein levels in LPS-stimulated RAW264.7 and BV2 cells. Taken together, the results of the present study suggest that 1 modulates several TLR4-mediated inflammatory pathways, demonstrating its potential in the treatment of inflammatory and neuroinflammatory conditions.

KEYWORDS:

Alternaramide; Anti-inflammation; MAPK; Marine-derived fungus; Nuclear factor-kappa B; Toll-like receptor 4

PMID:
26620692
DOI:
10.1016/j.cbi.2015.11.024
[Indexed for MEDLINE]

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