STAT1 and STAT3 are the main mediators of the signaling of interferons (IFNs) and of gp130 cytokines, respectively. Neoplastic T lymphocytes frequently become resistant to the IFN-gamma/STAT1 apoptotic pathway, often because of the downregulation of the IFN-gammaR2 receptor chain. Many studies suggest that cross-regulation between different STATs, in particular between STAT1 and STAT3, may profoundly affect cytokine/growth factor signaling. Here, the function of STAT3 in the negative regulation of STAT1 apoptotic pathway was investigated by RNA interference-mediated STAT3 silencing in human malignant T lymphocytes. In STAT3-depleted cells, interleukin (IL)-6 acquired the capacity to induce apoptosis, correlating with prolonged STAT1 activation and the induction of major histocompatibility complex (MHC) class I expression. In contrast, in the absence of STAT3, IFN-gamma could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-gamma, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes transplanted into severe combined immunodeficient mice. Therefore, treatment with IL-6 and simultaneous STAT3 silencing may represent a potential therapeutic approach to control the expansion of IFN-gamma-unresponsive neoplastic T cells.

IL-6, but not IFN-gamma, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing

REGIS, GABRIELLA;CONTI, Laura;CHIARLE, Roberto;PIVA, Roberto;GIOVARELLI, Mirella;POLI, Valeria;NOVELLI, Francesco
2009-01-01

Abstract

STAT1 and STAT3 are the main mediators of the signaling of interferons (IFNs) and of gp130 cytokines, respectively. Neoplastic T lymphocytes frequently become resistant to the IFN-gamma/STAT1 apoptotic pathway, often because of the downregulation of the IFN-gammaR2 receptor chain. Many studies suggest that cross-regulation between different STATs, in particular between STAT1 and STAT3, may profoundly affect cytokine/growth factor signaling. Here, the function of STAT3 in the negative regulation of STAT1 apoptotic pathway was investigated by RNA interference-mediated STAT3 silencing in human malignant T lymphocytes. In STAT3-depleted cells, interleukin (IL)-6 acquired the capacity to induce apoptosis, correlating with prolonged STAT1 activation and the induction of major histocompatibility complex (MHC) class I expression. In contrast, in the absence of STAT3, IFN-gamma could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-gamma, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes transplanted into severe combined immunodeficient mice. Therefore, treatment with IL-6 and simultaneous STAT3 silencing may represent a potential therapeutic approach to control the expansion of IFN-gamma-unresponsive neoplastic T cells.
2009
23
2102
2108
http://www.nature.com/leu/journal/vaop/ncurrent/pdf/leu2009139a.pdf
STAT3; STAT1; IL-6; IFN-; T lymphocytes
Regis G; Icardi L; Conti L; Chiarle R; Piva R; Giovarelli M; Poli V; Novelli F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/64084
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