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J Nat Prod. 2019 Jan 17. doi: 10.1021/acs.jnatprod.8b00939. [Epub ahead of print]

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

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Department of Pharmacognosy and Molecular Basis of Phytotherapy , Medical University of Warsaw , Warsaw 02-097 , Poland.
Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI) , University of Innsbruck , Innsbruck 6020 , Austria.
Institute of Genetics and Animal Breeding of the Polish Academy of Science , Jastrzębiec 05-552 , Poland.
Department of Pharmacognosy , University of Vienna , Vienna 1010 , Austria.
Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna 1090 , Austria.
Department of Zoology , University of Sargodha , Sargodha 40010 , Pakistan.
Department of Pharmacodynamics, Faculty of Pharmacy , Medical University of Warsaw , Warsaw 02-097 , Poland.
Institute of Pharmacology, Department of Phytochemistry , Polish Academy of Sciences , Kraków 30-024 , Poland.


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.

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