Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family

Progression of inflammatory processes correlates with the release of cell-d erived mediators from the local site of inflammation. These mediators, incl uding cytokines of the IL-1 and IL-6 families, act on host cells and exert their action by activating their signal transduction pathways leading to sp ecific target gene activation. Parthenolide, a sesquiterpene lactone found in many medical plants, is an inhibitor of IL-1-type cytokine signaling tha t blocks the activation of NF-kappa B, Here we show that parthenolide is al so an effective inhibitor of IL-6-type cytokines. It inhibits IL-6-type cyt okine-induced gene expression by blocking STAT3 phosphorylation on Tyr705. This prevents STAT3 dimerization necessary for its nuclear translocation an d consequently STAT3-dependent gene expression. This is a new molecular mec hanism of parthenolide action that additionally explains its anti-inflammat ory activities. (C) 2000 Academic Press.