Sesquiterpene lactones (SL) derived from Mexican India medicinal plants and parthenolide, the major SL from European feverfew, have raised considerable interest because of their anti-inflammatory and complex pharmacological action. Interleukin-4 (IL-4) is a key cytokine that influences the development of T helper 2 cells and plays an important role in the pathogenesis of allergic diseases. We show here that the anti-inflammatory parthenolide suppresses IL-4 expression at the mRNA and the protein levels in a dose-dependent manner. We demonstrate that parthenolide blocks NF-kappaB binding to two important IL-4 promoter regulatory elements and suppresses promoter activity upon T cell activation. Differences regarding the effects of parthenolide on expression levels of IL-4, IL-2 and IFN-gamma were observed. Parthenolide (2.5 microM) could completely suppress IL-4 protein levels secreted in anti-CD3/CD28-stimulated peripheral blood T cells from allergic and normal donors. Complete inhibition of IL-2 and IFN-gamma requires higher doses of parthenolide. So far, drugs directed against IL-4 expression have not been described. This finding raises the potential to develop parthenolide to treat IL-4-mediated allergic-like inflammation.