title: Interleukin 6 mediates production of interleukin 10 in metastatic melanoma.
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.
authors.affiliation: Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.|Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA, 19107, USA.|Department of Bioinformatics, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Mizue
authors.initials: M
authors.lastname: Terai
authors.affiliation: Department of Molecular Physiology and Biophysics, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Masumi
authors.initials: M
authors.lastname: Eto
authors.affiliation: Department of Molecular Physiology and Biophysics, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Garbo D
authors.initials: GD
authors.lastname: Young
authors.affiliation: Cancer Treatment Center of America, Philadelphia, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Berd
authors.affiliation: Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA, 19107, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mastrangelo
authors.affiliation: Department of Bioinformatics, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Molecular and Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harigaya
authors.affiliation: Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA, 19107, USA. takami.sato@jefferson.edu.|Department of Bioinformatics, Chiba University Graduate School of Medicine, Chiba, Japan. takami.sato@jefferson.edu.
authors.forename: Takami
authors.initials: T
authors.lastname: Sato
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D053612:Janus Kinases