Sesquiterpene lactones as inhibitors of IL-8 expression in HeLa cells.
Twenty-four structurally different SLs were studied for their inhibition on IL-8 production in HeLa229 cells and different IC50-values were obtained. QSAR analyses revealed that the alpha-methylene-gamma-lactone and the presence and reactivity of a second reaction center, expressed by LUMO2, are the most important descriptors for IL-8. Using two SLs as examples, we demonstrated that SLs prevent DNA binding of AP-1, which has binding sites in the IL-8 promoter together with NF-kappaB and C/EBP, and that this is probably due to directly targeting AP-1. p38 MAPK, which plays a role in AP-1 activation as well as in IL-8 regulation, was not influenced by SLs. These data show that NF-kappaB and AP-1, and consequently IL-8 may be interesting targets in antiinflammation research and that the small molecules of SLs may be powerful candidates with promising properties for therapeutic modulation of the inflammatory response.
Lindenmeyer
Maja T
MT
Institute of Pharmaceutical Science, Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany.
Hrenn
Andrea
A
Kern
Claudia
C
Castro
Victor
V
Murillo
Renato
R
Müller
Stefan
S
Laufer
Stefan
S
Schulte-Mönting
Jürgen
J
Siedle
Bettina
B
Merfort
Irmgard
I
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D017931:DNA Primers; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D007783:Lactones / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012717:Sesquiterpenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D016209:Interleukin-8; D007783:Lactones; D016328:NF-kappa B; D012333:RNA, Messenger; D012717:Sesquiterpenes