Parthenolide inhibits activation of signal transducers and activators of transcription (STATs) induced by cytokines of the IL-6 family.
Progression of inflammatory processes correlates with the release of cell-derived mediators from the local site of inflammation. These mediators, including cytokines of the IL-1 and IL-6 families, act on host cells and exert their action by activating their signal transduction pathways leading to specific target gene activation. Parthenolide, a sesquiterpene lactone found in many medical plants, is an inhibitor of IL-1-type cytokine signaling that blocks the activation of NF-kappaB. Here we show that parthenolide is also an effective inhibitor of IL-6-type cytokines. It inhibits IL-6-type cytokine-induced gene expression by blocking STAT3 phosphorylation on Tyr705. This prevents STAT3 dimerization necessary for its nuclear translocation and consequently STAT3-dependent gene expression. This is a new molecular mechanism of parthenolide action that additionally explains its anti-inflammatory activities.
Sobota
R
R
Institute of Molecular Biology, Jagiellonian University, 3 Mickiewicza Avenue, Krakow, 31-120, Poland.
Szwed
M
M
Kasza
A
A
Bugno
M
M
Kordula
T
T
D000209:Acute-Phase Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008113:Liver Neoplasms; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D000514:alpha 1-Antichymotrypsin / Q000235:genetics
D000209:Acute-Phase Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; C508351:OSM protein, human; D010455:Peptides; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012717:Sesquiterpenes; D015534:Trans-Activators; D000514:alpha 1-Antichymotrypsin; D053683:Oncostatin M; C002669:parthenolide