Journal
JOURNAL OF NATURAL PRODUCTS
Volume 82, Issue 2, Pages 375-385Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.8b00939
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Funding
- Polish Ministry of Science and Higher Education (MNiSW)
- Austrian Federal Ministry of Science, Research and Economy (BMWFW) in the frame of a Polish-Austrian cooperation of Medical University of Warsaw [FW25/RN1/14]
- Austrian Federal Ministry of Science, Research and Economy (BMWFW) in the frame of a Polish-Austrian cooperation of Austrian Agency for International Cooperation in Education and Research, OeAD-GmbH [PL13/2015]
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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 mu M) inhibited IL-8 and TNF-alpha 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 beta 2 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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