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

• Published in: Biochemical pharmacology 2018-08, Vol.154, p.384-396
• Main Authors: Yang, Shun-Chin, Chen, Po-Jen, Chang, Shih-Hsin, Weng, Yu-Ting, Chang, Fang-Rong, Chang, Kuang-Yi, Chen, Chun-Yu, Kao, Ting-I, Hwang, Tsong-Long
• Format: Article
• Language: English
• Subjects: Animals; Arthritis - drug therapy; Arthritis - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Edema - drug therapy; Edema - metabolism; Elastase; Flavone; Humans; Luteolin; Luteolin - pharmacology; Luteolin - therapeutic use; Male; Mice; Mice, Inbred C57BL; Neutrophil Activation - drug effects; Neutrophil Activation - physiology; Neutrophil extracellular traps; 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; Reactive oxygen species
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2018.06.003

[Display omitted] 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.