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Inhibition of IL-6+IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist, Sant 7, in breast tissue-derived fibroblasts.

Abstract：

: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.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Purohit A,Singh A,Ghilchik MW,Serlupi-Crescenzi O,Reed MJ

doi

10.1038/sj.bjc.6600785

subject

Has Abstract

pub_date

2003-02-24 00:00:00

pages

630-5

issue

eissn

0007-0920

issn

1532-1827

pii

6600785

journal_volume

pub_type

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Inhibition of IL-6+IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist, Sant 7, in breast tissue-derived fibroblasts.