Background Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic triglyceride content and increased inflammatory macrophage infiltration through the C-C motif chemokine receptor (CCR) 5 pathway in the liver. DA-6034 (7-carboxymethyloxy-3',4',5-trimethoxy flavone), is a synthetic derivative of eupatilin that exhibits anti-inflammatory activity in inflammatory bowel disease. However, the effect of DA-6034 on the inflammatory response in NAFLD is not well elucidated. Therefore, we aimed to determine the effect of DA-6034 on hepatic steatosis and inflammation.
Methods Forty male C57BL/6J mice were divided into the following four groups: (1) regular diet (RD), (2) RD with DA-6034, (3) high fat diet (HFD), and (4) HFD with DA-6034. All mice were sacrificed 12 weeks after the start of the experiment. The effects of DA-6034 on macrophages were assessed using RAW264.7 cells.
Results DA-6034 not only reduced hepatic triglyceride levels and lipid accumulation but also macrophage infiltration and proinflammatory cytokines in HFD-fed mice. According to fluorescence-activated cell sorter analysis, DA-6034 reduced the CD8+ T cell fraction in the liver of HFD-fed mice. DA-6034 also reduced CCR5 expression and the migration of liver macrophages in HFD-fed mice and inhibited CCR2 ligand and CCR4 ligand, which stimulated the migration of macrophages.
Conclusion Overall, DA-6034 attenuates hepatic steatosis and inflammation in obesity by regulating CCR5 expression in macrophages.
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Methods Harvested human peripheral blood mononuclear cells were treated with phytohemagglutinin and lipopolysaccharide, and murine peritoneal macrophages were stimulated with interleukin (IL)-1β for the evaluation of Sulf-1 and Sulf-2 expression. Sulf expression in inflammatory cells was examined in the human rheumatoid arthritis (RA) synovium by immunofluorescence staining. The antigen presentation and phagocytic activities of macrophages were compared according to the expression state of Sulfs. Sulfs-knockdown macrophages and Sulfs-overexpressing macrophages were generated using small interfering RNAs and pcDNA3.1 plasmids for Sulf-1 and Sulf-2, respectively.
Results Lymphocytes and monocytes showed weak Sulf expression, which remained unaffected by IL-1β. However, peritoneal macrophages showed increased expression of Sulfs upon stimulation with IL-1β. In human RA synovium, two-colored double immunofluorescent staining of Sulfs and CD68 revealed active upregulation of Sulfs in macrophages of inflamed tissues, but not in lymphocytes of lymphoid follicles. Macrophages are professional antigen-presenting cells. The antigen presentation and phagocytic activities of macrophages were dependent on the level of Sulf expression, suppressed in Sulfs-knockdown macrophages, and enhanced in Sulfs-overexpressing macrophages.
Conclusion The results demonstrate that upregulation of Sulfs in macrophages occurs in response to inflammation, and Sulfs actively regulate the antigen presentation and phagocytic activities of macrophages as novel immune regulators.
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