Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 44, Issue 3, Pages 379-388Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.b20-00752
Keywords
Lycium barbarum polysaccharide; pyruvate kinase 2 (PKM2); inflammation; glycolysis; macrophage differentiation; ubiquitination
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Funding
- Natural Science Foundation projects of Ningxia Autonomous Region [2019AAC03230]
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The study found that Lycium barbarum polysaccharide can suppress LPS-induced inflammation by modulating glycolysis and M1 differentiation of macrophages. This effect is mediated by downregulating PKM2 expression and enhancing ubiquitination.
Lipopolysaccharide (LPS)-induced inflammation is the leading cause of multiple organ failure in sepsis. Pyruvate kinase 2 (PKM2) is a protein kinase and transcriptional coactivator that plays an important role in glycolysis. Recent studies have confirmed that glycolysis maintains the M1 differentiation and induces immune activation in macrophages. Lycium barbarum polysaccharide (LBP), the main hioactive component of Chinese wolfberrv, suppresses glycolysis and inflammation. Here, RAW264.7 macrophages were treated with LBP for evaluating its effects against LPS-induced inflammation. The differentiation of M1/M2 macrophages was assessed by flow cytometry for assessing the cell surface markers, CD86 and CD206. The enrichment of hypoxia inducible factor (HIF)-1 alpha and ubiquitin in the PKM2 protein complex was determined by co-immunoprecipitation. LBP suppressed LPS-induced glycolysis, differentiation of Ml macrophages, and the production of interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and high mobility group (HMG) 1 proteins. The suppressive effects of LBP were similar to those of PKM2 knockdown, but were abolished by the overexpression of PKM2. LPS elevated the mRNA and protein levels of PKM2. LBP reduced the LPS-induced expression of PKM2 protein, but had no effects on the expression of PKM2 mRNA. LPS inhibited the ubiquitination of PKM2, probably by downregulating the expression of ubiquitin ligases, including Nedd4L, Nedd4, and Gnb2. LBP interfered with the inhibition of PKM2 ubiquitination by upregulating the expression of Nedd4L, Nedd4, and Gnb2. In conclusion, LBP suppressed the LPS-induced inflammation by altering glycolysis and the M1 differentiation of macrophages. The effects of LBP were mediated by the downregulation of PKM2 via enhanced ubiquitination.
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