INHIBITION OF THE EXPRESSION OF INDUCIBLE CYCLOOXYGENASE AND PROINFLAMMATORY CYTOKINES BY SESQUITERPENE LACTONES IN MACROPHAGES CORRELATES WITH THE INHIBITION OF MAP KINASES

In our previous studies (Refs. 1 and 2), it was shown that protein tyr osine kinase (PTK) inhibitors, radicicol and herbimycin A, inhibit the expression of the mitogen-inducible cyclooxygenase (COX-2) and proinf lammatory cytokines. Radicicol and herbimycin A possess polarized doub le bonds which can conjugate sulphydryl groups of proteins. Parthenoli de, the predominant sesquiterpene lactone in European feverfew (Tanace tum parthenium), contains alpha-methylene-gamma-lactone (MGL) and an e poxide in its structure. These moieties can interact with biological n ucleophiles such as a sulfhydryl group. Parthenolide inhibited the exp ression of COX-2 and proinflammatory cytokines (TNF alpha and IL-1) in lipopolysaccharide (LPS)-stimulated macrophages. The structure-functi on relationship indicates that the MGL moiety confers the inhibitory e ffect. Parthenolide suppressed LPS-stimulated protein tyrosine phospho rylation in the murine macrophage cell line (RAW 264.7). This suppress ion 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 inhibiti on. (C) 1996 Academic Press, Inc.