• Wonmin Ko, Jae Hak Sohn, Jae-Hyuk Jang, Jong Seog Ahn, Dae Gill Kang, Ho Sub Lee, Jong-Su Kim, Youn-Chul Kim, and Hyuncheol Oh.
• College of Pharmacy, Wonkwang University, Iksan 570-749, Republic of Korea.
• Chem. Biol. Interact. 2016 Jan 25; 244: 16-26.

AbstractAlternaramide (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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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