Abstract
20-Hydroxy-3-oxolupan-28-oic acid (HOA), a lupane-type triterpene, was obtained from the leaves of Mahonia bealei, which is described in the Chinese Pharmacopeia as a remedy for inflammation and related diseases. The anti-inflammatory mechanisms of HOA, however, have not yet been fully elucidated. Therefore, the objective of this study was to characterize the molecular mechanisms of HOA in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. HOA suppressed the release of nitric oxide (NO), pro-inflammatory cytokine tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in LPS-stimulated RAW264.7 macrophages without affecting cell viability. Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) analysis indicated that HOA also suppressed the gene expression of inducible NO synthase (iNOS), TNF-α, and IL-6. Further analyses demonstrated that HOA inhibited the phosphorylation of upstream signaling molecules, including p85, PDK1, Akt, IκBα, ERK, and JNK, as well as the nuclear translocation of nuclear factor κB (NF-κB) p65. Interestingly, HOA had no effect on the LPS-induced nuclear translocation of activator protein 1 (AP-1). Taken together, these results suggest that HOA inhibits the production of cytokine by downregulating iNOS, TNF-α, and IL-6 gene expression via the downregulation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs), and the inhibition of NF-κB activation. Our findings indicate that HOA could potentially be used as an anti-inflammatory agent for medical use.
Highlights
The inflammatory response is initiated in living tissues in defense of harmful stimuli, including invading microorganisms, irritants, or noxious chemicals [1]
The result of an MTT assay showed that Hydroxy-3-oxolupan-28-oic acid (HOA) had no significant cytotoxic effects at concentrations up to 40 μM (Figure 2A)
The nitric oxide (NO) content was determined by Griess reagent and the production of cytokines were measured by cytometric bead array (CBA) kit using the flow cytometry
Summary
The inflammatory response is initiated in living tissues in defense of harmful stimuli, including invading microorganisms, irritants, or noxious chemicals [1]. Macrophages are major inflammatory and immune effector cells that play crucial roles in producing cytokines, chemokines, and inflammatory mediators, including nitric oxide (NO), prostaglandin E2 , hydrolytic enzymes, and pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) [6,7]. These pathophysiological changes initiate signal transducers, such as phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinases (MAPKs), or Janus kinase/signal transducer and activator of transcription (JAK-STATs) to boost the activation and nuclear translocation of transcription factors, such as nuclear factor κB (NF-κB), activator protein 1 (AP-1), and STATs [8,9]. The development of a potential anti-inflammatory drug derived from natural products based on NF-κB target isolation is a promising avenue for research
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