Sesquiterpene lactone Zaluzanin D alters MMP-9 promoter methylation in differentiated THP-1 monocytic cells and down regulates inflammatory cytokines IL-1β and TNF-α

• Published in: International immunopharmacology 2020-10, Vol.87, p.106803-106803, Article 106803
• Main Authors: Cheeran, Vinnie, Munuswamy-Ramanujam, Ganesh
• Format: Article
• Language: English
• Subjects: Anti-inflammatory agents; Arteriosclerosis; Atherosclerosis; Cell differentiation; Cytokines; Deoxyribonucleic acid; Derivatives; DNA; DNA methylation; Enzyme-linked immunosorbent assay; Epigenetics; Flow cytometry; Fluorescence; Gelatinase A; Gelatinase B; IL-1β; Inflammation; Interleukins; Lactones; Lipids; Matrix metalloproteinase; Matrix metalloproteinases; Monocytes; Polymerase chain reaction; Reactive oxygen species; Sesquiterpene lactone; Sesquiterpene lactones; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Zaluzanin D
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106803

[Display omitted] •Anti-inflammatory effects of Zaluzanin D on PMA activated THP-1 monocytes.•Biotransformation on ZD’s lead to the loss of it’s anti-inflammatory activity.•ZD reduced cellular adhesion, intracellular ROS, and lipid accumulation in cells.•ZD decreased the expression of MMP-9, MMP-2, TNF-α and IL-1β levels.•ZD treatment caused hypermethylation of the MMP-9 gene promoter in THP-1 cells. Zaluzanin D (ZD) is a sesquiterpene lactone isolated from the leaves of Vernonia arborea. Earlier studies have highlighted the Sesquiterpene lactones (SLs) as molecules of medicinal value. The current study investigates the anti-inflammatory potential of ZD and its biotransformed derivatives in PMA differentiated human monocytic THP-1 cells. ZD and its fungal biotransformed derivatives Zaluzanin C (ZC) and 11,13- dihydrozaluzanin C (DZC) were screened for anti-inflammatory activity using their IC50 concentration. ZD showed significant ability to reduce PMA mediated THP-1 activation, while both ZC and DZC did not show any anti-inflammatory activity. Further studies revealed that ZD had ability to attenuate intracellular reactive oxygen species production in THP-1 cells as confirmed with FACS and fluorescence microscope experiments. Similarly, Oil red O (ORO) assay showed ability of ZD to inhibit lipid accumulation in monocytes. ZD also significantly reduced the expression of pro-inflammatory markers, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, MMP (Matrix metalloproteinases)-9 and MMP-2 as observed with RT-PCR and ELISA. Interestingly the molecule ZD also partially reversed DNA methylation levels in the PMA activated THP-1 cells. This indicated the ability of ZD to influence the epigenetic machinery of the cell. Overall the current study indicates that ZD has ability to attenuate inflammation in differentiated human THP-1 cells by regulating genes involved in the atherosclerosis inflammatory pathway. Thus ZD could potentially be used to modulate inflammation in atherosclerosis like disorders wherein monocytes play a key role.