A New IL-6-Inducing Mechanism in Cancer with New Therapeutic Possibilities

Background: Interleukin-6 is dysregulated in multiple pathological conditions, e.g., cancer and inflammatory diseases. Aim: To investigate new mechanisms for the regulation of pathological IL-6 production. Methods: PBMCs (peripheral blood mononuclear cells) stimulated by cancer serum factors or specific peptides produce interleukin-6 (IL-6). Immunoregulatory albumin neo-structures and peptides were identified with 2D gel electrophoresis and MALDI-TOF-MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) analyses. Il-6 and albumin neo-structures were determined by ELISA (enzyme-linked immunosorbent assay). Results: Conformational changes in normal serum albumin by proteolytic degradation generates an IL-6-inducing neo-structure, IL-6-inducing factor (IL-6IF). This neo-structure is immunogenic which results in the production of autoantibodies. IL-6 production induced by IL-6IF and cancer patient sera is inhibited by specific antibodies. The serum concentration of IL-6IF is significantly higher in advanced cancer stages, and its presence is significantly correlated with the survival of the patients. Conclusions: A new mechanism for the induction IL-6 synthesis is presented. Based on this mechanism, the pathological IL-6 production related to enhanced proteolytic activity can be diagnosed and selectively inhibited by specific antibodies. Such antibodies were identified and purified. Thus, the neo-structure, inducing pathological IL-6 production, associated with a reduced survival of cancer patients, can be selectively removed by the therapeutic administration of antibodies leaving the function of IL-6 needed for the normal activity of the immune system intact.