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Interleukin 6 mediates production of interleukin 10 in metastatic melanoma

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Abstract

We previously reported that substantial amounts of IL-10, an immunomodulatory cytokine, are produced by cell suspensions of fresh human metastatic melanoma tissues. Production diminished with continuous culturing of cells, which suggests a pivotal interactive role between melanoma cells and the tumor microenvironment. In this study, we found that the culture media obtained from LPS-stimulated peripheral blood mononuclear cells induced IL-10 production by metastatic melanoma cells. Of the multiple cytokines present in the conditioned culture media, IL-6 was identified as the inducer of IL-10 production. A neutralizing antibody against IL-6 completely blocked the conditioned medium-induced IL-10 production. Metastatic melanoma cells that constitutively produce low amount of IL-10 increased IL-10 production in response to recombinant human IL-6 in a dose-dependent fashion. The response to exogenously added IL-6 was less significant in melanoma cells that produced high amounts of IL-6, probably due to pre-existing autocrine stimulation of IL-10 by endogenous IL-6. On the other hand, metastatic melanoma cells that do not constitutively produce IL-10 protein did not respond to exogenous IL-6. In IL-6-responsive melanoma cells, IL-6 increased STAT3 phosphorylation and inhibition of STAT3 signaling using siRNA or inhibitors for JAKs diminished IL-6-induced IL-10 production. In addition, inhibition of MEK and PI3K, but not mTOR, interfered with IL-10 production. Taken together, the data suggest that blocking of these signals leading to IL-10 production is a potential strategy to enhance an anti-melanoma immune response in metastatic melanoma.

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Acknowledgments

We thank Dr. Andrew Aplin at Kimmel Cancer Center of Thomas Jefferson University and Dr. Matthew J. McGinniss at Caris Life Sciences for analysis of BRAF and NRAS mutations on melanoma cell lines. We also thank Dr. Henry C. Maguire, Jr. for critical review of this article. This research was supported by the Bonnie Kroll Research Fund, the Marla Brecher Research Fund, and the Eye Melanoma Research Fund at Thomas Jefferson University. M Eto and G. D. Young were supported by a Pennsylvania CURE grant.

Conflicts of Interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan

    Mizue Terai & Kenichi Harigaya

  2. Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA, 19107, USA

    Mizue Terai, Michael J. Mastrangelo & Takami Sato

  3. Department of Molecular Physiology and Biophysics, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA

    Masumi Eto & Garbo D. Young

  4. Cancer Treatment Center of America, Philadelphia, PA, USA

    David Berd

  5. Department of Bioinformatics, Chiba University Graduate School of Medicine, Chiba, Japan

    Mizue Terai, Yutaka Tamura & Takami Sato

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  1. Mizue Terai
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  2. Masumi Eto
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Correspondence to Takami Sato.

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Terai, M., Eto, M., Young, G.D. et al. Interleukin 6 mediates production of interleukin 10 in metastatic melanoma. Cancer Immunol Immunother 61, 145–155 (2012). https://doi.org/10.1007/s00262-011-1084-5

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  • DOI: https://doi.org/10.1007/s00262-011-1084-5

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