Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway

Our previous report has shown that FGF21 has anti-inflammatory properties in a collagen-induced arthritis (CIA) model. In this study, the underlying molecular mechanisms of action were also investigated using RAW 264.7 cells, a murine monocyte-macrophage. RAW 264.7 cells were pre-incubated with vari...

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Published in:International immunopharmacology 2016-09, Vol.38, p.144-152
Main Authors: Yu, Yinhang, He, Jinjiao, Li, Siming, Song, Liying, Guo, Xiaochen, Yao, Wenbing, Zou, Dehua, Gao, Xinyu, Liu, Yunye, Bai, Fuliang, Ren, Guiping, Li, Deshan
Format: Article
Language:English
Subjects:
Animals
Arthritis, Experimental - immunology
Cytokines - metabolism
FGF21
Fibroblast Growth Factors - immunology
Fibroblast Growth Factors - metabolism
Heme Oxygenase-1 - metabolism
Inflammation
Lipopolysaccharides - immunology
LPS
Macrophages - metabolism
Membrane Proteins - metabolism
Mice
NF-E2-Related Factor 2 - metabolism
NF-kappa B - metabolism
NF-κB
Nrf2-mediated anti-oxidant capacity
Oxidative Stress
RAW 264.7 Cells
RAW264.7 macrophages
Signal Transduction
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Summary:Our previous report has shown that FGF21 has anti-inflammatory properties in a collagen-induced arthritis (CIA) model. In this study, the underlying molecular mechanisms of action were also investigated using RAW 264.7 cells, a murine monocyte-macrophage. RAW 264.7 cells were pre-incubated with various concentrations (2000, 500, 100ng/ml) of FGF21 and stimulated with LPS to induce oxidative stress and inflammation. The result of flow cytometry showed that β-Klotho, FGF21 specific receptor, was expressed in murine splenic macrophages and RAW 264.7. In vitro, FGF21 reduced the expression of TNF-α, IL-1β, IL-6 and IFN-γ and increased the level of IL-10 in a dose-dependent manner in LPS-stimulated RAW 264.7 macrophages. FGF21 also suppressed profound elevation of ROS production and oxidative stress, as evidenced by an increase of the MDA level and depletion of the intracellular GSH level, and restored the activities of antioxidant enzymes SOD and GSH-Px in LPS-stimulated RAW 264.7 macrophages. Moreover, FGF21 inhibited LPS-induced nuclear factor-κB (NF-κB) activation, including degradation of I-κB and nuclear translocation of p65. In addition, the result of Western blot and real-time PCR showed that FGF21 induced heme oxygenase-1 (HO-1) expression and increased the nuclear transcription factor-E2–related factor 2 (Nrf2) levels in a dose-dependent manner in LPS-stimulated RAW 264.7 macrophages. In conclusion, the results suggest that macrophages are the targets for the anti-inflammatory effects of FGF21, and FGF21 exerted an anti-inflammatory effect mainly via enhancing Nrf2-mediated anti-oxidant capacity and suppressing NF-κB signaling pathway. •β-Klotho is expressed in macrophages of the spleen and RAW264.7.•FGF21 regulated cytokines expression in LPS-stimulated RAW264.7 macrophages.•FGF21 suppressed oxidative stress in LPS-stimulated RAW 264.7 macrophages.•FGF21 inhibited NF-κB activation in LPS-stimulated RAW 264.7 macrophages.•FGF21 induced HO-1 expression and increased Nrf2 levels in RAW264.7 macrophages.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2016.05.026