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Antioestrogens enhance tumour necrosis factor receptor 2 (TNF-R2) expression and TNF-R2-mediated proliferation in
1Turku Immunology Centre, Department of Medical Microbiology, Turku University, Finland.
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).
Insights
Non-steroidal antioestrogens like toremifene and tamoxifen inhibit T cell proliferation but enhance tumor necrosis factor receptor 2 (TNF-R2) expression and function, revealing a novel mechanism of action for these drugs.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Non-steroidal antioestrogens, such as tamoxifen and toremifene, are widely used in cancer therapy.
- Their effects on immune cells, particularly T cells, are not fully understood.
- Tumor necrosis factor receptor (TNF) family molecules play critical roles in immune responses.
Purpose of the Study:
- To investigate the impact of toremifene and tamoxifen on T cell proliferation and TNF receptor expression.
- To elucidate the role of the c-Jun amino terminal kinase (JNK) pathway in mediating these effects.
- To explore the functional consequences of altered TNF-R2 expression in antioestrogen-treated T cells.
Main Methods:
- Treatment of peripheral blood T cells with toremifene and tamoxifen.
- Assessment of mitogen-induced proliferation and cell surface receptor expression.
- Analysis of the c-Jun amino terminal kinase (JNK) pathway activation using anisomycin and phorbol 12-myristate 13-acetate (PMA).
Main Results:
- Toremifene and tamoxifen inhibited mitogen-induced T cell proliferation.
- Antioestrogens increased the surface expression of tumor necrosis factor receptor 2 (TNF-R2) on activated T cells.
- This up-regulation enhanced TNF-R2-mediated proliferation.
- Inhibition of JNK activity by anisomycin down-regulated TNF-R2, while toremifene inhibited PMA-induced JNK activity.
Conclusions:
- Antioestrogens exert novel effects on T cells by up-regulating TNF-R2 expression and enhancing its-mediated proliferation.
- The JNK pathway is implicated in the regulation of TNF-R2 expression by antioestrogens.
- Antioestrogens modulate T cell responses through inhibition of protein kinase C (PKC) and influence on signaling pathways like JNK.