Sodium Salicylate Modulates Inflammatory Responses Through AMP-activated Protein Kinase Activation In LPS-stimulated THP-1 Cells

?Background? Sodium salicylate(Na Sal)is a nonsteroidal anti-inflammatory drug.The putative mechanisms for Na Sal's pharmacologic action include the inhibition of cyclooxygenases,platelet-derived thromboxane A2 and NF-?B signaling.Recent studies demonstrated that salicylate could activate AMP-activated protein kinase(AMPK),an energy sensor that maintains the balance between ATP production and consumption.The anti-inflammatory action of AMPK has been reported to be mediated by promoting mitochondrial biogenesis and fatty acid oxidation.However,the exact signals responsible for salicylate-mediated inflammation through AMPK are not well-understood.?Purpose? The purpose of this study was to investigate the potential effects of AMPK activated by Na Sal on inflammation-like responses of THP-1 monocytes to lipopolysaccharide(LPS)challenge.?Methods? THP-1 cells were stimulated with or without 10ug/ml LPS for 24 h in the presence or absence of 5m M Na Sal.Apoptosis was measured by flow cytometry using Annexin V/PI staining and by western blotting for Bcl-2.Cell proliferation was detected by Ed U incorporation and b y western blot analysis for proliferating cell nuclear antigen(PCNA).Secretion of pro-inflammatory cytokines(TNF-?,IL-1?,and IL-6)was determined by enzyme-linked immunosorbent assay(ELISA).?Results? Activation of AMPK by Na Sal was accompanied by induction of apoptosis,inhibition of cell proliferation and increasing secretion of TNF-? and IL-1? in LPS-stimulated THP-1 cells.These effects were reversed by Compound C,an inhibitor of AMPK.In addition,Na Sal/AMPK activation inhibited LPS-induced STAT3 phosphorylation,which was reversed by Compound C treatment.?Conclusion? AMPK activation is important for Na Sal-mediated inflammation by inducing apoptosis,reducing cell proliferation,inhibiting STAT3 activity,and producing TNF-? and IL-1?.