The estrogen metabolite 17beta-dihydroequilenin counteracts interleukin-1alpha induced expression of inflammatory mediators in human endothelial cells in vitro via NF-kappaB pathway.
In most studies showing cardio- and vasculoprotective effects of estrogens, 17beta-estradiol was used and little information on possible effects of different estrogen metabolites is yet available. We investigated whether particular estrogen metabolites are effective in counteracting inflammatory activation of human endothelium. Human endothelial cells were incubated with 17alpha-dihydroequilenin, 17beta-dihydroequilenin, delta-8,9-dehydroestrone, estrone and 17beta-estradiol and stimulated with interleukin (IL)-1alpha. The expression of IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) was determined. 17beta-dihydroequilenin and 17beta-estradiol at a concentration of 1 microM reduced IL-1alpha-induced up regulation of IL-6, IL-8 and MCP-1 close to control levels. When both compounds were used in combination an additive effect was observed. 17alpha-dihydroequilenin and delta-8,9-dehydroestrone showed a similar anti-inflammatory effect only when used at 10 microM whereas estrone had no effect. The effect of 17beta-dihydroequilenin on IL-1alpha-induced production of IL-6, IL-8 and MCP-1 was reversed by the estrogen receptor antagonist ICI 182,780. 17beta-dihydroequilenin also inhibited IL-1alpha-induced translocation of p50 and p65 to the nucleus of the cells. We have identified the estrogen metabolite 17beta-dihydroequilenin, as an inhibitor of inflammatory activation of human endothelial cells. Characterization of specific estrogens--as shown in our study--could provide the basis for tailored therapies, which might be able to achieve vasoprotection without adverse side effects.
Department of Internal Medicine II, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Svitlana
S
Demyanets
Stefan
S
Pfaffenberger
Christoph
C
Kaun
Gersina
G
Rega
Walter S
WS
Speidl
Stefan P
SP
Kastl
Thomas W
TW
Weiss
Philipp J
PJ
Hohensinner
Wolf
W
Dietrich
Walter
W
Tschugguel
Valery N
VN
Bochkov
Ezzat M
EM
Awad
Gerald
G
Maurer
Kurt
K
Huber
Johann
J
Wojta
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004857:Equilin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D000077267:Fulvestrant; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D004857:Equilin; D000077267:Fulvestrant; D004958:Estradiol; C014482:dihydroequilin