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 inflammatory and immune response. Therefore, components of the NF-kappa B-activating signaling pathways are frequent targets for antiinflammatory agents. This study shows that the sesquiterpene lactone parthenolide inhibits a common step in NF-kappa B activation by preventing the TNF-alpha-induced induction of I kappa B kinase (IKK) and IKK beta, without affecting the activation of p38 and c-Jun N-terminal kinase. Parthenolide impairs NF-kappa B-dependent transcription triggered by expression of TNFR-associated factor-2, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEKK1), and NF-kappa B-inducing kinase. This compound also prevents activation of both IKKs and DNA binding of NF-kappa B induced by MEKK and NF-kappa B-inducing kinase. Parthenolide targets a component of the I kappa B kinase complex without directly inhibiting IKK alpha, IKK beta, or MEKK1. Therefore, this sesquiterpene lactone could serve as a lead compound for the development of antiinflammatory remedies and is suitable as a molecular tool, allowing the dissection of TNF-alpha-derived signaling pathways leading to the activation of NF-kappa B, c-Jun N-terminal kinase, and p38.
Hehner
S P
SP
Department of Immunochemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hofmann
T G
TG
Dröge
W
W
Schmitz
M L
ML
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C002669:parthenolide; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C482576:MAP3K1 protein, human