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

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Abstract:

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 (TNFalpha 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.

Document Type: Research Article

Affiliations: 1: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana, 70808 2: Department of Chemistry, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana, 70808

Publication date: September 1, 1996

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