Therapeutic strategy for inflammatory diseases by a novel negative regulatory transcriptional factor of inflammatory cytokines

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Prolonged production of inflammatory cytokines including IL-lb from monocytes/ macrophages in the tissue is a major pathological feature of Rheumatoid Arthritis (RA). Regarding the transcriptional regulation of IL-lb gene, we revealed the importance of promoter sequences immediately upstream of the transcription start site (cap site) and identified the element located position between-3134 and -2729 was required for maximal LPS and PMA induction. The enhancer region also involved in the increase transcription of IL-lb gene in human monocytic cell line THP-1, murine macrophage cell line RAW 267.4 cells as well as-RA synovial cells, synovial cell line Ell. Using a serial CAT plasmid including these mitogen responsive elements, we also found negative regulatory region located between-2833 and-2782. The deletion of the element resulted in the augmentation of transcription of IL-lb gene in both THP-1 and RAW 267.4 cells but not in Ell. We conducted electrophoretic mobility shift assay using 32P-labeled oligonucleotides of the negative regulatory element. A single band was enhanced by LPS, PMA stimulation and not competed by antibodies for conventional transcriptional factors including jun and fos families and NFkB.