Inflammation Research

, Volume 67, Issue 5, pp 445–453 | Cite as

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

  • Eun Jung Park
  • Young Min Kim
  • Hye Jung Kim
  • Ki Churl Chang
Original Research Paper



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.


Heme oxygenase Inflammation Sepsis Acute lung injury HMGB1 



High-mobility group box 1


Heme oxygenase-1


Acute lung injury


Zinc protoporphyrin IX


Extracellular signal-regulated protein kinase


c-Jun NH2-terminal kinase


Nuclear factor-κB


Mitogen-activated protein kinase


Nitric oxide




Pathogen-associated molecular pattern


Damage-associated molecular pattern


Nuclear factor (erythroid-derived 2)-like 2


Antioxidant response element


Thiazolyl blue tetra-zolium bromide


Dimethyl sulfoxide


Polyvinylidene difluoride






Carbon monoxide


Phosphoinositide 3-kinase



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).

Author contributions

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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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Eun Jung Park
    • 1
  • Young Min Kim
    • 1
  • Hye Jung Kim
    • 1
  • Ki Churl Chang
    • 1
  1. 1.Department of Pharmacology and Institute of Health Sciences, School of MedicineGyeongsang National UniversityJinjuRepublic of Korea

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