In vivo modulation of murine serum tumour necrosis factor and interleukin-6 levels during endotoxemia by oestrogen agonists and antagonists.
Oestrogen has been reported to modulate tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6 cytokine levels in human mononuclear cell cultures. In the present study, the effects of exogenous oestrogen administration on the cytokine response to an endotoxin challenge was investigated in a murine model of endotoxemia. Animals pretreated for 4 days with 17 alpha ethinyl oestradiol exhibited divergent regulation of TNF and IL-6 levels in sera from endotoxin-stimulated mice. Oestrogen treatment resulted in a significant increase in serum TNF while serum IL-6 levels, relative to the placebo group, decreased in response to an endotoxin challenge. These oestrogenic effects were dose dependent with maximal elevations observed in TNF at 1 mg/kg and maximal reduction in IL-6 at 0.1 mg/kg of 17 alpha ethinyl oestradiol. The increase in TNF levels by ethinyl oestradiol was blocked by co-administration of the oestrogen receptor antagonist tamoxifen. Oestrogen-mediated modulation of the TNF and IL-6 response to endotoxin was also apparent in animals implanted with 17 beta oestradiol pellets. The oestrogen-mediated effects on serum IL-6 were consistent with a reduction in IL-6 mRNA in peritoneal macrophages from oestrogen-treated mice. The effects of oestrogen on TNF and IL-6 production were also investigated in vitro. Oestradiol-treated macrophage cultures produced three- to fourfold lower amounts of IL-6 without any significant modulatory effects on TNF secretion. The combined in vivo and in vitro results demonstrate the modulation of IL-6 and TNF during endotoxemia by oestrogen analogues through an oestrogen receptor-dependent mechanism.
Zuckerman
S H
SH
Division of Cardiovascular Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Bryan-Poole
N
N
Evans
G F
GF
Short
L
L
Glasebrook
A L
AL
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004926:Escherichia coli; D045166:Estradiol Congeners / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000097:blood; D012772:Shock, Septic / Q000097:blood*; D013629:Tamoxifen / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D004967:Estrogens; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; D004997:Ethinyl Estradiol