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Transcriptional Control and Signal Transduction

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

Leukemia volume 23, pages 2102–2108 (2009)Cite this article

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-γ/STAT1 apoptotic pathway, often because of the downregulation of the IFN-γR2 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-γ could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-γ, 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-γ-unresponsive neoplastic T cells.

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Acknowledgements

This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Compagnia di San Paolo (special project Oncology), Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), ex 40% and Fondo per gli Investimenti della Ricerca di Base (FIRB), Ministero della Salute, Progetto integrato Oncologia; Regione Piemonte: Ricerca Industriale e Sviluppo Precompetitivo (ONCOPROT), Ricerca Industriale ‘Converging Technologies’ (BIOTHER), Ricerca Sanitaria Finalizzata, by a fellowship from FIRB (GR).

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Author notes

  1. G Regis

    Present address: 4Current address: Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.,

Authors and Affiliations

  1. The Center for Experimental Research and Medical Studies (CERMS), San Giovanni Battista Hospital—Molinette, Turin, Italy

    G Regis, L Icardi, L Conti, R Chiarle, R Piva, M Giovarelli & F Novelli

  2. Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy

    G Regis, L Conti, M Giovarelli & F Novelli

  3. Department of Genetics, The Molecular Biotechnology Center (MBC), Biology and Biochemistry, University of Turin, Turin, Italy

    G Regis & V Poli

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  1. G Regis
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  2. L Icardi
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  3. L Conti
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Correspondence to F Novelli.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Regis, G., Icardi, L., Conti, L. et al. IL-6, but not IFN-γ, triggers apoptosis and inhibits in vivo growth of human malignant T cells on STAT3 silencing. Leukemia 23, 2102–2108 (2009). https://doi.org/10.1038/leu.2009.139

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