Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: Abrogation of constitutive monocyte chemoattractantprotein-1 production

IL-6 is synthesized in human pampilloma virus (HPV)-transformed cervical ca rcinoma 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 carc inoma cell lines expressed high IL-6 levels. However, these carcinoma cell lines showed low responsiveness to IL-6 as revealed by low constitutive STA T3 binding activity, which was not further enhanced by exogenous IL-6. In c ontrast, in vitro-transformed nonmalignant keratinocytes without endogenous IL-6 production strongly responded to exogenous IL-6 with activation of ST AT3. STAT3 protein expression levels were comparable in both responsive and nonresponsive cell lines. Also, gp130, the upstream signal-transducing rec eptor subunit conveying IL-6 signals into the cell, was expressed in all te sted cell lines. However, the IL-6 binding subunit gp80 was lost in the mal ignant cells. Addition of soluble gp80 was sufficient to restore IL-6 respo nsiveness in carcinoma cells as shown by enhanced activation of STAT3 bindi ng activity. As a consequence of the restored IL-6 responsiveness, carcinom a 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 l imited gp80 expression. While production of IL-6 might contribute to a loca l immunosuppressive effect, silencing an autocrine IL-6 response prevents c onstitutive production of the mononuclear cell-attracting chemokine MCP-1. Both mechanisms might help the tumor to escape the immune system.