4'­O­Methylalpinumisoflavone inhibits the activation of monocytes/macrophages to an immunostimulatory phenotype induced by 27­hydroxycholesterol.

ABSTRACT

The epidemiological, animal and cell effects of plant metabolites suggest versatile health benefits of flavonoids. However, whether flavonoids affect the deleterious biological activity of oxygenated cholesterol molecules remains to be elucidated. The present study investigated the effects of 4'­O­methylalpinumisoflavone (mAI) isolated from Maclura tricuspidata (Cudrania tricuspidata) on the 27­hydroxycholesterol (27OHChol)­induced activation of monocytes/macrophages using human THP­1 cells. mAI dose­dependently impaired the expression of C­C motif chemokine ligand (CCL)2 chemokine and the migration of monocytic cells enhanced by 27OHChol. mAI downregulated the surface and cellular levels of CD14 and inhibited the release of soluble CD14. This isoflavone significantly weakened the lipopolysaccharide responses that were enhanced in the presence of 27OHChol, and inhibited the transcription and secretion of the active gene product of matrix metalloproteinase­9. mAI also suppressed the expression of C­C motif chemokine receptor 5 ligands, including CL3 and CCL4, and M1­phenotype markers induced by 27OHChol. Furthermore, mAI impaired phosphorylation of the nuclear factor­κB p65 subunit without affecting the phosphorylation of Akt. These results indicate that mAI inhibits the activation of monocytes/macrophages to the immunostimulatory phenotype in a milieu rich in 27OHChol, suggesting potential benefits of the flavonoid for the treatment of diseases in which the pathogenesis is linked to 27OHChol­induced inflammatory responses.