Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 21; pp. 7534 - 7539
• Main Authors: Jang, Saebyeol, Kelley, Keith W, Johnson, Rodney W
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.05.2008; National Acad Sciences
• Subjects: Animals; Antioxidants; Binding sites; Biological Sciences; Brain; Brain - drug effects; Brain - immunology; Cell lines; Cells; Cells, Cultured; Cytokines; DNA - metabolism; Encephalitis - immunology; Epithelial cells; Flavonoids; I-kappa B Kinase - metabolism; Interleukin-6 - blood; Interleukin-6 - genetics; Interleukin-6 - metabolism; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Luteolin - pharmacology; Male; Messenger RNA; Mice; Mice, Inbred BALB C; Microglia; Microglia - drug effects; Microglia - immunology; Neurons; NF-kappa B - metabolism; Phosphorylation; Phosphorylation - drug effects; Potable water; Promoter Regions, Genetic - drug effects; Protein Binding - drug effects; RNA, Messenger - metabolism; Rodents; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0802865105

Luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce production of proinflammatory mediators in LPS-stimulated macrophages, fibroblasts, and intestinal epithelial cells. Because excessive production of proinflammatory cytokines by activated brain microglia can cause behavioral pathology and neurodegeneration, we sought to determine whether luteolin also regulates microglial cell production of a prototypic inflammatory cytokine, IL-6. Pretreatment of primary murine microlgia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. To determine how luteolin inhibited IL-6 production in microglia, EMSAs were performed to establish the effects of luteolin on LPS-induced binding of transcription factors to the NF-κB and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-κB DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of IκB-α but inhibited JNK phosphorylation. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 h after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation.