Proliferatins suppress lipopolysaccharide-induced inflammation via inhibition of the NF-κB and MAPK signaling pathways

Three previously undescribed polyketides [proliferatin A-C (1-3)] with anti-inflammatory activity were isolated from Fusarium proliferatum. 1-3 attenuated the production of inflammatory signal messengers including nitric oxide (NO), reactive oxygen species, proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta), as well as the related proteins nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Transcriptome analyses based on RNA-seq indicated the potential anti-inflammatory mechanism of 1-3 involved in the nuclear factor kappa-B (NF-kappa B) and mitogen activated protein kinases (MAPKs) signaling pathways. Experimental evaluation of the protein levels revealed that 1-3 can inhibit the phosphorylation of I kappa B kinase (IKK), the degradation of NF-kappa B Inhibitor-alpha (I kappa B alpha), the phosphorylation of nuclear factor-kappa B (NF-kappa B) and can reduce NF-kappa B transportation to the nucleus. Interestingly, 1-3 decreased the phosphorylation of MAPKs including p-p38, pERK, and p-JNK. Molecular docking models suggest that binding of 1-3 to TLR4-MD-2 complex may lead to inhibition of NF-kappa B and MAPK signaling pathways, which was confirmed in vitro by surface plasmon resonance (SPR) assays. 1-3 can thus constitute potential therapeutic candidates for the treatment of inflammation associated diseases.