COSTUNOLIDE AND DEHYDROCOSTUS LACTONE AS INHIBITORS OF KILLING FUNCTION OF CYTOTOXIC T-LYMPHOCYTES

Costunolide and dehydrocostus lactone were isolated from an extract of mokko (Saussurea en lappa Clarke) as inhibitors of killing activity of cytotoxic T lymphocytes (CTL). Mokko lactone was also isolated as an inactive compound from the extract, The structure-activity relationship indicated that alpha-methylene-gamma-butyrolactone is required for the inhibitory effect, Costunolide markedly inhibited the granule exocytosis and the production of inositol phosphates in response to anti-CD3 monoclonal antibody (mAb) stimulation at a concentration that did not affect the binding of anti-CD3 mAb, Tyrosine phosphorylation induced by crosslinking of CD3 molecules was significantly inhibited by costunolide in a dose-dependent manner, These results suggest that costunolide inhibits the killing activity of CTL through preventing the increase in tyrosine phosphorylation in response to the crosslinking of T-cell receptors.