Metformin Inhibits Chemokine Expression Through the AMPK/NF-kappa B Signaling Pathway

Inflammation is mediated by cytokines and chemokines, which are considered targets of inflammatory diseases. Mounting evidence has demonstrated the anti-inflammatory benefits of metformin. However, the underlying mechanisms are not completely understood. In this study, we aim to elucidate the regulatory effects of metformin on chemokine expression and the possible mechanisms using RAW264.7 cells, a mouse macrophage cell line, as a model. First, we treated the cells with lipopolysaccharide (LPS), and found that the expression of CXCL10 and CXCL11 was markedly induced in a dose- and time-dependent fashion concurrent with the inhibition of AMPK activity. Then, we treated the cells with metformin, and analyzed the expression of CCL2, CXCL10, and CXCL11 by quantitative real-time polymerase chain reaction (PCR). We observed that metformin prevented the stimulating effect of LPS on these chemokines as well as IL-1 and IL-6. Second, the inhibitory effects of metformin on LPS-induced chemokine expression were diminished by Compound C, a chemical inhibitor of AMPK. Finally, we investigated whether the NF-B signaling pathway is regulated by metformin in this setting. Our results showed that metformin inhibited the phosphorylation of I-B and p65 while it activated AMPK. Therefore, the results suggest that metformin inhibits LPS-induced chemokine expression through the AMPK and NF-B signaling pathways.