The sesquiterpene lactone parthenolide inhibits LPS- but not TNF-α-induced maturation of human monocyte-derived dendritic cells by inhibition of the p38 mitogen-activated protein kinase pathway

Background: Dendritic cells (DCs) are the most potent antigen-presenting cells, and the manipulation of DC maturation provides a strategy for the treatment of allergic and inflammatory diseases. Objective: In this study we examined the effect of the anti-inflammatory sesquiterpene lactone parthenolide (PTL) on DC maturation induced by LPS or TNF-α. Methods: Human monocyte-derived DCs generated by means of culture with GM-CSF and IL-4 were pretreated with PTL and subsequently stimulated with LPS or TNF-α. Results: PTL inhibited the upregulation of CD80, CD83, CD86, CD40, and MHC class II; the allostimulatory function; the production of TNF-α and IL-12; and the downregulation of FITC-labeled dextran uptake in human monocyte-derived DCs stimulated with LPS but not with TNF-α. The inhibitory effect of PTL on DC maturation was preceded by inhibition of the phosphorylation of p38 mitogen-activated protein kinase but not the nuclear translocation of NF-κB. Conclusion: These results might offer PTL not only as a promising compound for the treatment of LPS-induced disorders, including sepsis or septic shock, by inhibition of excessive DC maturation but also as a tool to further dissect the signaling pathways involved in DC maturation. (J Allergy Clin Immunol 2002;110:269-76.)