Comparative analysis of immunomodulatory effects of Artemisinin and Parthenolide on activation of immune cells and their roles in Salmonella Typhimurium infection

Plant-derived immunomodulators are of immense therapeutic interest, of which sesquiterpene lactones (SLs) are a promising source. Artemisinin and Parthenolide are two structurally related SLs that are known to inhibit NF-{kappa}B. However, whether this mechanism produces comparable immunomodulatory outcomes has not been directly examined. In this study, we compared the effects of Artemisinin and Parthenolide across different in vitro and in vivo inflammatory contexts: T-cell activation, macrophage activation, and Salmonella Typhimurium infection. Parthenolide inhibited mouse T-cell activation more effectively than Artemisinin in terms of cell cycling, IL-2 production, and induction of activation markers, CD69 and CD44. In addition, Parthenolide suppressed production of LPS-induced nitrite and pro-inflammatory cytokines in primary thioglycolate (TG)-elicited macrophages as well as RAW 264.7 cells. It also reduced ROS production across all tested conditions. In contrast, Artemisinin exhibited comparatively modest effects, although it increased IL-6 in LPS-activated RAW 264.7 cells. Neither compound reduced bacterial burden in an in vitro model of S. Typhimurium infection; however, Parthenolide, but not Artemisinin, lowered TNF- amounts. Together, these findings demonstrate that Parthenolide is a broader and more consistent immunomodulator than Artemisinin. These observations led us to investigate the effects of Parthenolide in an in vivo model of mice orally fed with S. Typhimurium. Parthenolide-treated mice showed higher survival accompanied with lower sera amounts of IL-6 and TNF-, indicating that its protective effects operate by limiting host immunopathology. The implications of these observations on the use of compounds that lower host inflammatory responses during infections are discussed.