Eupatoriopicrin Inhibits Pro-inflammatory Functions of Neutrophils via Suppression of IL‑8 and TNF-alpha Production and p38 and ERK 1/2 MAP Kinases

• Published in: Journal of natural products (Washington, D.C.) Vol. 82; no. 2; pp. 375 - 385
• Main Authors: Michalak, Barbara, Piwowarski, Jakub P, Granica, Sebastian, Waltenberger, Birgit, Atanasov, Atanas G, Khan, Shafaat Y, Breuss, Johannes M, Uhrin, Pavel, Żyżyńska-Granica, Barbara, Stojakowska, Anna, Stuppner, Hermann, Kiss, Anna K
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 22.02.2019
• Subjects: aerial parts; Apoptosis - drug effects; CD18 antigen; CD18 Antigens - antagonists & inhibitors; Cells, Cultured; Eupatorium cannabinum; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; fractionation; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - physiology; Humans; inflammation; inhibitory concentration 50; interleukin-8; Interleukin-8 - antagonists & inhibitors; Interleukin-8 - biosynthesis; lead; lipopolysaccharides; mice; mitogen-activated protein kinase; neutrophils; Neutrophils - drug effects; Neutrophils - physiology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; peritonitis; phosphorylation; Plant Extracts - pharmacology; Reactive Oxygen Species - metabolism; respiratory tract diseases; screening; Sesquiterpenes - metabolism; Sesquiterpenes - pharmacology; sesquiterpenoid lactones; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/acs.jnatprod.8b00939

During chronic inflammation, neutrophils acting locally as effector cells not only activate antibacterial defense but also promote the inflammatory response. Interleukin 8 (IL-8), the main cytokine produced by activated neutrophils, positively correlates with the severity of respiratory tract diseases. By screening European plants traditionally used for treating respiratory tract diseases, we found that extracts of aerial parts of Eupatorium cannabinum inhibit IL-8 release from neutrophils. Using bioassay-guided fractionation, we identified five sesquiterpene lactones, eupatoriopicrin (1), 5′-deoxyeupatoriopicrin (2), hiyodorilactone A (3), 3-hydroxy-5′-O-acetyleupatoriopicrin = hiyodorilactone D (4), and hiyodorilactone B (5), that efficiently (IC50 < 1 μM) inhibited IL-8 and TNF-α release in lipopolysaccharide (LPS)-stimulated human neutrophils. Moreover, all these sesquiterpene lactones suppressed the adhesion of human neutrophils to an endothelial monolayer by downregulating the expression of the β2 integrin CD11b/CD18 on the neutrophil surface. Furthermore, eupatoriopicrin efficiently suppressed LPS-induced phosphorylation of p38 MAPK and ERK and attenuated neutrophil infiltration in the thioglycolate-induced peritonitis model in mice. Altogether, these results demonstrate the potential of the sesquiterpene lactone eupatoriopicrin as a lead substance for targeting inflammation.