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

Abstract

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-B and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-B DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of I B-␣ 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.cytokines ͉ flavonoids ͉ MAPK ͉ brain ͉ neuroinflammation

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

“…4). Inhibition of JNK phosphorylation was reported to reduce production of these proinflammatory cytokines (29,30). These data, together with our finding that Mtb Eis acetylates DUSP16/MKP-7 at Lys55, indicate that Mtb Eis suppresses host innate immune responses through inactivation of JNK via acetylation of DUSP16/MKP-7.…”

Flavones Inhibit LPS-Induced Atrogin-1/MAFbx Expression in Mouse C2C12 Skeletal Myotubes

“…Although the effects of flavonoids on the NF-kB inflammatory pathway have received considerable attention, the expression of the inflammatory cytokine IL-6 is mediated by an activator protein-1 (AP-1) regulatory element in addition to NF-kB (27). Furthermore, Jang et al reported that luteolin inhibited LPS-induced IL-6 production in microglia by inhibiting JNK phosphorylation (28). Our results also showed that pretreatment with apigenin and luteolin significantly inhibits LPS-induced JNK phosphorylation in C2C12 myotubes.…”

MicroRNA-92a Negatively Regulates Toll-like Receptor (TLR)-triggered Inflammatory Response in Macrophages by Targeting MKK4 Kinase

“…MKK4 is activated by the majority of MKKKs, such as ASK, MEKK, and TAK (8), and preferentially phosphorylates the tyrosine residue of JNKs, which are required for optimal JNK activation (63). JNK can be strongly activated in multiple cell types by LPS or inflammatory cytokines and regulates AP-1 transcription factor activity and the production of inflammatory cytokines (64,65). Previous studies demonstrated that MKK7, but not MKK4, is essential for IL-1-mediated JNK activation in cultured fibroblast-like synoviocytes (52).…”