Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte chemoattractant protein-1 production.
IL-6 is synthesized in human papilloma virus (HPV)-transformed cervical carcinoma cell lines and is supposed to stimulate these cells in an autocrine manner. We studied IL-6 production and responsiveness in nonmalignant HPV-transformed keratinocytes and cervical carcinoma cells in detail. IL-6 was detected in cervical carcinomas in situ. Correspondingly, HPV-positive carcinoma cell lines expressed high IL-6 levels. However, these carcinoma cell lines showed low responsiveness to IL-6 as revealed by low constitutive STAT3 binding activity, which was not further enhanced by exogenous IL-6. In contrast, in vitro-transformed nonmalignant keratinocytes without endogenous IL-6 production strongly responded to exogenous IL-6 with activation of STAT3. STAT3 protein expression levels were comparable in both responsive and nonresponsive cell lines. Also, gp130, the upstream signal-transducing receptor subunit conveying IL-6 signals into the cell, was expressed in all tested cell lines. However, the IL-6 binding subunit gp80 was lost in the malignant cells. Addition of soluble gp80 was sufficient to restore IL-6 responsiveness in carcinoma cells as shown by enhanced activation of STAT3 binding activity. As a consequence of the restored IL-6 responsiveness, carcinoma cells strongly produced the chemokine monocyte chemoattractant protein-1 (MCP-1). Our data demonstrate that cervical carcinoma cells producing high amounts of IL-6 only weakly respond to IL-6 in an autocrine manner due to limited gp80 expression. While production of IL-6 might contribute to a local immunosuppressive effect, silencing an autocrine IL-6 response prevents constitutive production of the mononuclear cell-attracting chemokine MCP-1. Both mechanisms might help the tumor to escape the immune system.
Institute of Virology, University of Cologne, Cologne, Germany. s.hess@uni-koeln.de
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Hess
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Smola
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Sandaradura De Silva
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Hadaschik
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Kube
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Baldus
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Flucke
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Pfister
D017209:Apoptosis / Q000276:immunology; D019898:Autocrine Communication / Q000276:immunology*; D002278:Carcinoma in Situ / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019014:fas Receptor / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D019014:fas Receptor; D000093242:Interleukin-6 Inhibitors; C494086:STAT3 protein, human; C113250:interleukin-6 receptor alpha