Luteolin activates ERK1/2- and Ca2+-dependent HO-1 induction that reduces LPS-induced HMGB1, iNOS/NO, and COX-2 expression in RAW264.7 cells and mitigates acute lung injury of endotoxin mice
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Although luteolin has shown to have anti-inflammatory action, no report is available whether luteolin inhibits HMGB1 and protects acute lung injury (ALI) in endotoxin rodents. We hypothesized that HO-1 induction by luteolin might play a crucial role for inhibition of pro-inflammatory mediators including HMGB1 through MAPK signaling in LPS-induced RAW264.7 cells, and it ameliorates ALI of endotoxin mice.
The effects of luteolin on the production of pro-inflammatory mediators in LPS-activated RAW264.7 cells and LPS-injected mice were evaluated. The mechanisms were investigated using various signal inhibitors.
Luteolin significantly increased HO-1 expression through ERK1/2 signaling in a time- and concentration-dependent manner. Indeed, luteolin inhibited pro-inflammatory mediators (HMGB1, iNOS/NO, COX-2, and NF-κB activity) in LPS-activated RAW264.7 cells. In addition, PD98059, an ERK1/2 inhibitor, treatment failed to inhibit production of these pro-inflammatory mediators by luteolin. Interestingly, luteolin augmented HO-1 induction through Ca2+ influx in RAW264.7 cells. Administration of luteolin significantly inhibited plasma HMGB1 level, and iNOS expression in the lung that resulted in a significant reduction of ALI in endotoxin mice that was reversed by a HO-1 inhibitor, ZnPPIX.
Therefore, we conclude that luteolin has a great potential for treatment of ALI and related diseases, where HMGB1 is a therapeutic target.
KeywordsHeme oxygenase Inflammation Sepsis Acute lung injury HMGB1
High-mobility group box 1
Acute lung injury
Zinc protoporphyrin IX
Extracellular signal-regulated protein kinase
c-Jun NH2-terminal kinase
Mitogen-activated protein kinase
Pathogen-associated molecular pattern
Damage-associated molecular pattern
Nuclear factor (erythroid-derived 2)-like 2
Antioxidant response element
Thiazolyl blue tetra-zolium bromide
We thank Mr. Min S. Park for technical assistance. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2016R1A2B4008471).
Conceived of or designed study: Chang KC. Performed research: Park EJ. Analyzed data: Kim HJ and Chang KC. Contributed new methods or models: Park EJ and Kim YM. Wrote the paper: Chang KC.
Compliance with ethical standards
Conflict of interest
Authors have no conflict of interest to declare.
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