Inhibition of the Expression of Inducible Cyclooxygenase and Proinflammatory Cytokines by Sesquiterpene Lactones in Macrophages Correlates with the Inhibition of MAP Kinases

• DOI: 10.1006/bbrc.1996.1433
• Publication Date: 2002-09-16T10:49:55Z
• Authors: Daniel Hwang; Nikolaus H. Fischer; Byeong C. Jang; Heekyung Tak; Jin K. Kim; Wan Lee
• Keywords: Proinflammatory cytokine; Parthenolide; Sesquiterpene lactone

In our previous studies (Refs. 1 and 2), it was shown that protein tyrosine kinase (PTK) inhibitors, radicicol and herbimycin A, inhibit the expression of the mitogen-inducible cyclooxygenase (COX-2) and proinflammatory cytokines. Radicicol and herbimycin A possess polarized double bonds which can conjugate sulphydryl groups of proteins. Parthenolide, the predominant sesquiterpene lactone in European feverfew (Tanacetum parthenium), contains alpha-methylene-gamma-lactone (MGL) and an epoxide in its structure. These moieties can interact with biological nucleophiles such as a sulfhydryl group. Parthenolide inhibited the expression of COX-2 and proinflammatory cytokines (TNF alpha and IL-1) in lipopolysaccharide (LPS)-stimulated macrophages. The structure-function relationship indicates that the MGL moiety confers the inhibitory effect. Parthenolide suppressed LPS-stimulated protein tyrosine phosphorylation in the murine macrophage cell line (RAW 264.7). This suppression was correlated with its inhibitory effect on the expression of COX-2 and the cytokines. Among tyrosine phosphorylated proteins, mitogen-activated protein kinases (MAPKs) exhibited the most dramatic inhibition.