Induction of chromosomal aberrations and growth-transformation of lymphoblastoid cell lines by inhibition of reactive oxygen species-induced apoptosis with interleukin-6

Etiological evidence, indicating the relationships between the onset of mal ignant lymphoma and pre-existing chronic inflammation, has been accumulated . For the autonomous growth of malignant tumor, genetic lesions, such as ch romosomal aberrations, amplification of oncogenes, and mutations of genes i nvolved in the cell cycle regulation, must be essential. However, how the i nflammation promotes the accumulation of genetic lesions and induces the au tonomous growth of lymphoid cells remains unclear, Reactive oxygen species released by polymorphonuclear leukocytes and macrophages are factors causin g DNA damage in the foci of inflammation, and thus could play a role in lym phomagenesis. The xanthine/xanthine oxidase (X/XOD) system produces a mixtu re of hydrogen peroxide and superoxide anion extracellularly, and thus serv es as an in vitro source of reactive oxygen species. Cell death of lymphobl astoid cell lines (LCLs) was induced with X/XOD treatment in a dose-depende nt manner. DNA fragmentation, which is the characteristic feature of apopto sis, was observed in LCLs at 4-8 hours after X/XOD treatment. Among cytokin es such as interleukin-6 (IL-6), IL-10, and interferon-gamma, only pretreat ment with IL-6 gave LCLs the resistance to X/XOD-induced cell death in a do se-dependent manner. The proportion of apoptotic cells in X/XOD-treated LCL culture was decreased with IL-6 pretreatment by quantification with flow c ytometric analysis. Treatment of LCLs with IL-6 for 48 hours up-regulated b cl-2 mRNA expression. Furthermore, the LCLs repeatedly treated with X/XOD a nd cultured with or without IL-6 showed many more structural abnormalities of chromosomes than those without X/XOD treatment. Colony forming efficienc y of X/XOD-treated LCLs with IL-6 was significantly higher than those witho ut IL-6, and even relatively higher than LCLs without X/XOD treatment. IL-6 could support the survival of non-neoplastic B cells and accelerate the ma lignant transformation of B lineage cells in inflammatory lesions.