title: The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase.
abstract: BACKGROUND
  Biologically active natural products continue to be useful in the exploration and control of intracellular signaling processes. For example, the sesquiterpene lactone parthenolide from the anti-inflammatory medicinal herb Feverfew (Tanacetum parthenium) appears to inhibit the pro-inflammatory signaling pathway. Parthenolide's direct molecular target, however, remains unknown. We set out to identify the molecular mechanisms of parthenolide's anti-inflammatory activity.
  
  
  RESULTS
  A parthenolide affinity reagent was synthesized and shown to bind directly to and inhibit IkappaB kinase beta (IKKbeta), the kinase subunit known to play a critical role in cytokine-mediated signaling. Mutation of cysteine 179 in the activation loop of IKKbeta abolished sensitivity towards parthenolide. Moreover, we showed that parthenolide's in vitro and in vivo anti-inflammatory activity is mediated through the alpha-methylene gamma-lactone moiety shared by other sesquiterpene lactones.
  
  
  CONCLUSIONS
  In recent years, the multi-subunit IKK complex has been shown to be responsible for cytokine-mediated stimulation of genes involved in inflammation and as such represents an attractive target for pharmaceutical intervention. Our finding that parthenolide targets this kinase complex provides a possible molecular basis for the anti-inflammatory properties of parthenolide. In addition, these results may be useful in the development of additional anti-inflammatory agents.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520-8103, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Kwok
authors.forename: B
authors.initials: B
authors.lastname: Koh
authors.forename: M I
authors.initials: MI
authors.lastname: Ndubuisi
authors.forename: M
authors.initials: M
authors.lastname: Elofsson
authors.forename: C M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D019921:Biotinylation; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D020903:Tanacetum parthenium / Q000737:chemistry*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C002669:parthenolide; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse