Ulinastatin attenuates LPS-induced inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway

• 来源期刊: 中国药理学报（英文版）
• 关键词: ulinastatin inflammation LPS cytokines JNK NF-κB ROS PI3K/Akt Nrf2 RAW264.7 cells
• 年，卷（期）: 2018,（8）
• 页码范围: 1294-1304
• 页数: 11页
• 语种: 英文
• DOI: 10.1038/aps.2017.143

摘要

Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions,which is widely used for the treatment of various diseases,such as pancreatitis and sepsis.Although the therapeutic effects of UTI are reported to be associated with a variety of mechanisms,the signaling pathways mediating the antiinflammatory action of UTI remain to be elucidated.In the present study we carried out a systematic study on the anti-inflammatory and anti-oxidative mechanisms of UTI and their relationships in LPS-treated RAW264.7 cells.Pretreatment with UTI (1000 and 5000 U/mL) dose-dependently decreased the mRNA levels of pro-inflammatory cytokines (IL-1β,IL-6,TNF-α,iNOS) and upregulated anti-inflammatory cytokines (IL-10 and TGF-β1) in LPS-treated RAW264.7 cells.UTI pretreatment significantly inhibited the nuclear translocation of NF-κB by preventing the degradation of IκB-α.UTI pretreatment only markedly inhibited the phosphorylation of JNK at Thr183,but it did not affect the phosphorylation of JNK at Tyr185,ERK-1/2 and p38 MAPK;JNK was found to function upstream of the IκB-α/NF-κB signaling pathway.Furthermore,UTI pretreatment significantly suppressed LPS-induced ROS production by activating PI3K/Akt pathways and the nuclear translocation of Nrf2 via promotion of p62-associated Keap1 degradation.However,JNK was not involved in mediating the anti-oxidative stress effects of UTI.In summary,this study shows that UTI exerts both anti-inflammatory and anti-oxidative effects by targeting the JNK/NF-κB and PI3K/Akt/Nrf2 pathways.