Luteolin attenuates neutrophilic oxidative stress and inflammatory arthritis by inhibiting Raf1 activity

Shun-Chin Yang; Po-Jen Chen; Shih-Hsin Chang; Yu-Ting Weng; Fang-Rong Chang; Kuang-Yi Chang; Chun-Yu Chen; Ting-I Kao; Tsong-Long Hwang

doi:10.1016/j.bcp.2018.06.003

Luteolin attenuates neutrophilic oxidative stress and inflammatory arthritis by inhibiting Raf1 activity

Biochem Pharmacol. 2018 Aug:154:384-396. doi: 10.1016/j.bcp.2018.06.003. Epub 2018 Jun 6.

Authors

Shun-Chin Yang¹, Po-Jen Chen², Shih-Hsin Chang³, Yu-Ting Weng⁴, Fang-Rong Chang⁵, Kuang-Yi Chang⁶, Chun-Yu Chen⁷, Ting-I Kao⁸, Tsong-Long Hwang⁹

Affiliations

¹ Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan; Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
² Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Cosmetic Science, Providence University, Taichung 433, Taiwan.
³ Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
⁴ Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
⁵ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁶ Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan.
⁷ Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.
⁸ Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Division of Chinese Internal Medicine, Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
⁹ Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City 243, Taiwan. Electronic address: htl@mail.cgu.edu.tw.

PMID: 29883707
DOI: 10.1016/j.bcp.2018.06.003

Abstract

Neutrophils play a significant role in inflammatory tissue injury. Activated neutrophils produce reactive oxygen species (ROS), release proteases, and form neutrophil extracellular traps (NETs), significantly affecting the pathogenesis of inflammatory arthritis. We examined the therapeutic effects of luteolin, a flavone found in many plants, in neutrophilic inflammation and on acute inflammatory arthritis. Luteolin significantly inhibited superoxide anion generation, ROS production, and NET formation in human neutrophils. The increase in elastase release, CD11b expression, and chemotaxis was also inhibited by luteolin. Luteolin significantly suppressed phosphorylation of extracellular signal-regulated kinase (Erk) and mitogen-activated protein kinase kinase-1 (MEK-1), but not c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Analysis of the molecular mechanism further revealed that luteolin acts as a Raf-1 inhibitor. In mice with complete Freund's adjuvant-induced arthritis, luteolin ameliorated neutrophil infiltration as well as the thickness of paw edema and ROS production. In conclusion, in addition to its known ROS scavenging effect, this study is the first to provide evidence that luteolin diminishes human neutrophil inflammatory responses by inhibiting Raf1-MEK-1-Erk. Our results focused on the importance of neutrophil activation in inflammatory tissue injury and offer opportunities for the development of luteolin's therapeutic potential to attenuate neutrophilic inflammatory diseases.

Keywords: Elastase; Flavone; Luteolin; Neutrophil extracellular traps; Reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arthritis / drug therapy
Arthritis / metabolism*
Cells, Cultured
Dose-Response Relationship, Drug
Edema / drug therapy
Edema / metabolism
Humans
Luteolin / pharmacology
Luteolin / therapeutic use*
Male
Mice
Mice, Inbred C57BL
Neutrophil Activation / drug effects*
Neutrophil Activation / physiology
Neutrophils / drug effects
Neutrophils / metabolism
Oxidative Stress / drug effects*
Oxidative Stress / physiology
Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
Proto-Oncogene Proteins c-raf / metabolism*

Substances

Proto-Oncogene Proteins c-raf
Raf1 protein, rat
Luteolin