Tripathi reported that artemisinin reduced ICAM-1 expression in human brain microvascular endothelial cells (37)

Tripathi reported that artemisinin reduced ICAM-1 expression in human brain microvascular endothelial cells (37). use in the protection against the early development of atherosclerotic lesions. (11,12). Previous studies have also ML604440 indicated that the mitogen-activated protein kinase (MAPK) signaling pathway is involved in monocyte adhesion to human umbilical vein endothelial cells (HUVECs) (13). Artemisinin (C15H22O5), derived from the sweet wormwood reported that the NF-B and JNK pathways are related to VCAM-1 expression in lipopolysaccharide (LPS)-stimulated HUVECs (33), and Ju reported that p38 MAPK is involved in TNF–induced ICAM-1 and VCAM-1 expression in HUVECs (34). Moreover, in another study, p38 inhibitor decreased the protein level of ICAM-1 and VCAM-1 in TNF–stimulated HUVECs, while the ERK inhibitor had no effect on ICAM-1 and VCAM-1 expression (35). In this study, we investigated whether the MAPK signaling pathway is related to the adhesion of monocytes to HUVECs. We also examined the association between the MAPK signaling pathway and the expression of ICAM-1 and VCAM-1 in TNF–stimulated HUVECs. Both artemisinin and the NF-B inhibitor, Bay 11-7028, inhibited MAPK signaling pathway activation in TNF–stimulated HUVECs. Using specific inhibitors of MAPK (ERK, JNK and p38), we found that U0126 (ERK1/2 inhibitor) significantly decreased the adhesion of monocytes to HUVECs and the expression of ICAM-1 and VCAM-1, while SB203580 had a weaker effect and SP600125 had no effect, which indicated that ERK1/2 is the major MAPK responsible for the decreased adhesion of monocytes to HUVECs and the expression of ICAM-1 and VCAM-1 by artemisinin. Recently, artemisinin and its derivatives have attracted increasing attention due to their effects beyond their antimalarial properties. Our previous studies have demonstrated that artemisinin exerts anti-inflammatory effects in monocytes/macrophages through the MAPK and NF-B pathways (17,18). Cao reported that artemisinin blocked the proliferation, migration and inflammatory reaction induced by TNF- in vascular smooth muscle cells through the NF-B pathway (36). Tripathi reported that artemisinin reduced ICAM-1 expression in human brain microvascular endothelial cells (37). Artesunate, an artemisinin derivative, has been reported to abrogate the expression of ICAM-1 in parasitized red blood cell (pRBC)-stimulated endothelial cells and prevent pRBCs adhesion to vascular endothelial cells by impairing NF-B translocation to the nucleus (38). Another study demonstrated that dihydroarteannuin inhibited NF-B ML604440 translocation and ameliorated lupus symptoms in BXSB mice (39). Our data further indicated that artemisinin significantly decreased monocyte adhesion to TNF–stimulated HUVECs, and suppressed the mRNA and protein level of ICAM-1 and VCAM-1 in TNF–stimulated HUVECs through the NF-B and MAPK pathways. All these data indicate that artemisinin plays a significant role in atherosclerosis-related inflammation and lipid uptake, which exert protective effects against Nos1 the development and progression of atherosclerosis. In conclusion, in this study, we demonstrated that artemisinin inhibited the adhesion of monocytes to HUVECs and suppressed the expression of ICAM-1 and VCAM-1 in TNF–stimulated HUVECs (Fig. 6). The protective effects of artemisnin against adhesion are likely mediated through the suppression of the NF-B and MAPK pathways. These findings not only shed new light on the mechanisms of action of artemisinin, but also suggest that artemisinin may prove to be useful in the protection against the development of ML604440 early atherosclerotic lesions. Open in a separate window Figure 6 Artemisinin inhibits monocyte adhesion to human umbilical vein endothelial cells (HUVECs) through the nuclear factor-B (NF-B) and MAPK pathways. Acknowledgments This study was supported by the Fund of Science and Technology Commission of Shanghai Municipality (grants no. 12401905200) and the Fund of National Natural Science Foundation of China (grant nos. 81270376, 81470546 and 81500392). Abbreviations HUVECshuman umbilical vein endothelial cellsICAM-1intercellular adhesion molecule-1VCAM-1vascular cell adhesion molecule-1NF-Bnuclear factor-BTNF-tumor necrosis factor-pRBCsparasitized red blood cells.