The anti-inflammatory sesquiterpene lactone parthenolide suppresses CD95-mediated activation-induced-cell-death in T-cells.
Apoptosis is a morphologically distinct form of cell death involved in many physiological and pathological processes. The death receptor CD95 (APO-1/Fas) and its ligand (L) CD95L are critically involved in activation-induced-cell-death (AICD) of activated T-cells. Here we show that the anti-inflammatory sesquiterpene lactone parthenolide derived from the European traditional herb-medicine feverfew and many Mexican India medicinal plants suppresses expression of the CD95L and CD95 at the mRNA levels, thus, preventing T-cells from AICD. We demonstrate that parthenolide blocks NF-kappaB binding to the two NF-kappa binding sites of the CD95L promoter and suppresses promoter activity upon T-cell activation. Aberrant expression of CD95 and, particularly CD95L is dangerous and may lead to severe diseases. Our study indicates that parthenolide supports T-cell survival by down-regulating the CD95 system, at least in part, and, therefore, may have therapeutic potential as a new anti-apoptotic substance against AICD in T-cells.
Li-Weber
M
M
Tumorimmunology Program, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. m.li-weber@dkfz-heidelberg.de
Giaisi
M
M
Baumann
S
S
Treiber
M K
MK
Krammer
P H
PH
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011401:Promoter Regions, Genetic; D012717:Sesquiterpenes / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D012717:Sesquiterpenes; D019014:fas Receptor; C002669:parthenolide