Interleukin 6 mediates production of interleukin 10 in metastatic melanoma

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2012-02, Vol.61 (2), p.145-155
• Main Authors: Terai, Mizue, Eto, Masumi, Young, Garbo D., Berd, David, Mastrangelo, Michael J., Tamura, Yutaka, Harigaya, Kenichi, Sato, Takami
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Antibodies; Antibodies, Blocking - pharmacology; Antineoplastic agents; Autocrine signalling; Biological and medical sciences; Cancer Research; Cell culture; Cell suspensions; Cells, Cultured; Culture Media, Conditioned; Cytokines; Data processing; Dermatology; Drug dosages; Gene Expression Regulation, Neoplastic; Humans; Immune response; Immunology; Immunomodulation; Immunotherapy; Interleukin 10; Interleukin 6; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-6 - genetics; Interleukin-6 - immunology; Interleukin-6 - metabolism; Janus Kinases - antagonists & inhibitors; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Lipopolysaccharides - immunology; Lipopolysaccharides - metabolism; Lymphatic system; Lymphoma; MAP Kinase Signaling System - drug effects; Media (culture); Medical sciences; Medicine; Medicine & Public Health; Melanoma; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Metastases; Metastasis; Microenvironments; Neoplasm Metastasis; Oncology; Original; Original Article; Peripheral blood mononuclear cells; Pharmacology. Drug treatments; Phosphorylation; RNA, Small Interfering - genetics; siRNA; Skin cancer; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; TOR protein; Transcriptional Activation - drug effects; Tumor necrosis factor-TNF; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-011-1084-5

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.