Wedelolactone suppresses LPS-induced caspase-11 expression by directly inhibiting the IKK complex.
Caspase-11 is a key regulator of proinflammatory cytokine IL-1beta maturation and pathological apoptosis. Caspase-11 is not expressed in most tissues under normal condition, but highly inducible upon pathological stimulation such as in the presence of lipopolysaccharide (LPS). Here, we describe the identification and characterization of wedelolactone, a natural compound that inhibits LPS-induced caspase-11 expression in cultured cells by inhibiting NF-kappaB-mediated transcription. We demonstrate that wedelolactone is an inhibitor of IKK, a kinase critical for activation of NF-kappaB by mediating phosphorylation and degradation of IkappaBalpha.
Kobori
M
M
Department of Cell Biology, Harvard Medical School, Boston, MA, USA. kobori@hms.harvard.edu
Yang
Z
Z
Gong
D
D
Heissmeyer
V
V
Zhu
H
H
Jung
Y-K
YK
Gakidis
M Angelica M
MA
Rao
A
A
Sekine
T
T
Ikegami
F
F
Yuan
C
C
Yuan
J
J
D000818:Animals; D015415:Biomarkers; D020169:Caspases / Q000096:biosynthesis* / Q000187:drug effects; D053471:Caspases, Initiator; D002478:Cells, Cultured; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D036601:Eclipta / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D015415:Biomarkers; D003374:Coumarins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C440499:lipopolysaccharide, Escherichia coli O111 B4; C051122:wedelolactone; 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; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator