Antioestrogens Enhance Tumour Necrosis Factor Receptor 2 (TNF‐R2) Expression and TNF‐R2‐Mediated Proliferation in Activated T Cells

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Abstract
In the present study we demonstrate that the non‐steroidal antioestrogens toremifene and tamoxifen inhibit mitogen‐induced proliferation and up‐regulation of tumour necrosis factor (TNF) receptor family molecules on peripheral blood T cells. In activated T cells, however, toremifene and tamoxifen increase the surface expression of tumour necrosis factor receptor 2 (TNF‐R2). This up‐regulation is functionally important as TNF‐R2‐mediated proliferation is significantly enhanced in antioestrogen‐treated activated T cells. The regulation of TNF‐R2 expression in activated T cells seems to involve the c‐Jun amino terminal kinase (JNK) pathway, as activation of JNK with anisomycin down‐regulates TNF‐R2. In activated T cells toremifene clearly inhibits phorbol 12‐myristate 13‐acetate (PMA)‐induced JNK activity, suggesting that the JNK pathway may also be involved in the up‐regulation of TNF‐R2 expression by antioestrogens. Taken together, the enhancement of TNF‐R2 expression and TNF‐R2‐mediated proliferation in activated T cells represents a novel feature for the effects of antioestrogens. The inhibitory effects of toremifene on the JNK pathway demonstrates that antioestrogens can influence not only cell growth, but also a variety of other cellular responses by inhibiting protein kinase C (PKC).