The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex

The transcription factor NF-kappa B is a key regulator of the cellular infl ammatory and immune response. Therefore, components of the NF-kappa B activ ating signaling pathways are frequent targets for antiinflammatory agents. This study shows that the sesquiterpene lactone parthenolide inhibits a com mon step in NF-kappa B activation by preventing the TNF-alpha-induced induc tion of I kappa B kinase (IKK) and IKK beta, without affecting the activati on of p38 and c-Jun N-terminal. kinase, Parthenolide impairs NF-kappa B-dep endent transcription triggered by expression of TNFR-associated factor-2, m itogen-activated protein kinase/extracellular signal-regulated kinase kinas e (MEKK1), and NF-kappa B-inducing kinase, This compound also prevents acti vation of both IKKs and DNA binding of NF-kappa B induced by MEKK and NF-ka ppa B-inducing kinase, Parthenolide targets a component of the I kappa B ki nase complex without directly inhibiting IKK alpha, IKK beta, or MEKK1. The refore, this sesquiterpene lactone could serve as a lead compound for the d evelopment of antiinflammatory remedies and is suitable as a molecular tool , allowing the dissection of TNF-alpha-derived signaling pathways leading t o the activation of NF-kappa B, c-Jun N-terminal kinase, and p38.