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.
背景：白细胞介素-6在多种病理状态下（如癌症和炎症性疾病）存在表达失调。 目的：探究病理性IL-6产生调控的新机制。 方法：通过癌症血清因子或特定肽段刺激外周血单个核细胞产生白细胞介素-6。采用二维凝胶电泳和基质辅助激光解吸/电离飞行时间质谱技术鉴定免疫调节性白蛋白新结构与多肽。使用酶联免疫吸附法测定IL-6及白蛋白新结构水平。 结果：正常血清白蛋白经蛋白水解降解产生的构象变化可形成IL-6诱导新结构——IL-6诱导因子。该新结构具有免疫原性，可引发自身抗体产生。IL-6IF及癌症患者血清诱导的IL-6生成可被特异性抗体抑制。晚期癌症患者血清中IL-6IF浓度显著升高，其存在与患者生存期显著相关。 结论：本研究揭示了诱导IL-6合成的新机制。基于该机制，可通过特异性抗体诊断并选择性抑制与蛋白水解活性增强相关的病理性IL-6产生。此类抗体已完成鉴定与纯化。因此，通过治疗性抗体给药可选择性清除诱导病理性IL-6产生的新结构（该结构与癌症患者生存期缩短相关），同时保留免疫系统正常功能所需的IL-6活性。
A New IL-6-Inducing Mechanism in Cancer with New Therapeutic Possibilities
肿瘤(癌症)患者之家