Inhibition of IL-6+IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist, Sant 7, in breast tissue-derived fibroblasts.
Interleukin 6 (IL-6) and its soluble receptor (IL-6sR) can markedly stimulate aromatase activity in cultured fibroblasts derived from normal or malignant breast tissues. IL-6 acts by binding to a low-affinity membrane-spanning receptor (IL-6R), which must associate with a high-affinity receptor (gp130) for signal transduction to occur. Sant 7 is a mutated form of IL-6 that can bind to the IL-6R, but inhibits its ability to interact with the gp130 signal transducing protein. In this study, we have used Sant 7 to examine its ability to inhibit IL-6+IL-6 soluble receptor (IL-6sR)-stimulated aromatase activity in breast tissue-derived fibroblasts. As previously observed, IL-6+IL-6sR markedly stimulated aromatase activity (7.7-20.8-fold) in fibroblasts derived from reduction mammoplasty tissue, tissue proximal to tumours and breast tumours. Sant 7 inhibited basal aromatase activity in some fibroblasts by 25-30% that had a high basal activity, but almost completely blocked the ability of IL-6+IL-6sR to stimulate aromatase activity. The IC(50) for the inhibition of IL-6+IL-6sR-stimulated aromatase activity by Sant 7 was 60 ng ml(-1). A comparison of the effects of prostaglandin E(2) (PGE(2)), which can also regulate aromatase activity, and IL-6+IL-6sR revealed a greater degree of aromatase stimulation by IL-6+IL-6sR. Sant 7, however, inhibited PGE(2)-stimulated aromatase activity by 70% suggesting that PGE(2) acts, in part, by stimulating IL-6 production. Much of the IL-6 and IL-6sR available to stimulate breast tumour aromatase activity may originate from infiltrating macrophages and lymphocytes. The ability to block aromatase stimulation by these factors may offer a novel therapeutic strategy for reducing oestrogen synthesis in breast tumours.
Purohit
A
A
Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College, St. Mary's Hospital, London, UK.
Singh
A
A
Ghilchik
M W
MW
Serlupi-Crescenzi
O
O
Reed
M J
MJ
D001141:Aromatase / Q000378:metabolism*; D001940:Breast / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015850:Interleukin-6 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D001141:Aromatase; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors; C432252:SANT-7