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 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.
Hwang
D
D
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge 70808, USA.
Fischer
N H
NH
Jang
B C
BC
Tak
H
H
Kim
J K
JK
Lee
W
W
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D007375:Interleukin-1 / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D015394:Molecular Structure; D010946:Plants, Medicinal; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C002669:parthenolide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases