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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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Abstract

Objective

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.

Methods

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.

Results

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.

Conclusion

Therefore, we conclude that luteolin has a great potential for treatment of ALI and related diseases, where HMGB1 is a therapeutic target.

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Abbreviations

HMGB1:

High-mobility group box 1

HO-1:

Heme oxygenase-1

ALI:

Acute lung injury

ZnPPIX:

Zinc protoporphyrin IX

ERK1/2:

Extracellular signal-regulated protein kinase

JNK:

c-Jun NH2-terminal kinase

NF-κB:

Nuclear factor-κB

MAPK:

Mitogen-activated protein kinase

NO:

Nitric oxide

LPS:

Lipopolysaccharide

PAMP:

Pathogen-associated molecular pattern

DAMP:

Damage-associated molecular pattern

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

ARE:

Antioxidant response element

MTT:

Thiazolyl blue tetra-zolium bromide

DMSO:

Dimethyl sulfoxide

PVDF:

Polyvinylidene difluoride

PG:

Prostaglandin

IL:

Interleukin

CO:

Carbon monoxide

PI3K:

Phosphoinositide 3-kinase

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, 52527, Republic of Korea

    Eun Jung Park, Young Min Kim, Hye Jung Kim & Ki Churl Chang

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  1. Eun Jung Park
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  2. Young Min Kim
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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.

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Correspondence to Ki Churl Chang.

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Authors have no conflict of interest to declare.

Additional information

Communicated by John Di Battista.

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Park, E.J., Kim, Y.M., Kim, H.J. et al. 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. Inflamm. Res. 67, 445–453 (2018). https://doi.org/10.1007/s00011-018-1137-8

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  • DOI: https://doi.org/10.1007/s00011-018-1137-8

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