The transcriptional factor involved in the constitutive expression of interleukin-6 in multiple myeloma

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The purpose of this research project is to understand the pathogenesis of multiple myeloma by clarifying the mechanism of constitutive production of its autocrine growth factor, interleukin-6 (IL-6). It has been shown that, in human glioblastoma cell line SK-MG-4, IL-1 induced transcriptional activation of the IL-6 gene is mediated by a transcriptional factor NF-ILF6, which binds to a specific DNA sequence in the promoter region of the IL-6 gene. In order to test the possibility that NF-IL6 might be involved also in the constitutive expression of IL-6 in myeloma cells, we analyzed expression of both IL-6 and NF-IL6 mRNA in myeloma cells using the RT-PCR method. In all of the tested myeloma cells, including human myeloma cell lines, KMS-5 and U266 as well as primarily cultured myeloma cells, we could detect expression of both IL-6 and NF-IL6 mRNA, whose intensities were comparable to or even stronger than those of the human peripheral mononuclear cells stimulated with PHA and TPA. Moreover, we could detect NF-IL6 activity as a sequence specific DNA binding protein in nuclear extracts of those myeloma cells by gel shift assay probed with a synthetic oligonucleotide corresponding to a NF-IL6 binding sequence. In normal tissues, NF-IL6 mRNA is not expressed ordinarily, but expressed transiently upon stimulation with LPS or several cytokines, including IL-1. Our data showing the constitutive expression of NF-IL6 mRNA and activity in myeloma cells without any stimulation suggest the possibility that the constitutive expression of NF-IL6 may be responsible for the constitutive and deregulated production of IL-6 in myeloma cells.