Bcl6 Is a Transcriptional Repressor for theIL-18Gene

Abstract

Bcl6 functions as a sequence-specific transcriptional repressor, and Bcl6-deficient (Bcl6−/−) mice have been reported to display Th2-type inflammatory diseases in multiple organs. Since IL-18 is a potent stimulator of Th2 cells, we examined the expression of IL-18 mRNA in bone marrow-derived macrophages from Bcl6−/− mice after LPS stimulation. Here we show that the expression was strikingly up-regulated after stimulation. The expression was also up-regulated in RAW264 cells, a murine macrophage cell line, by transfection with the dominant negative type of Bcl6 gene. We identified a putative Bcl6-binding DNA sequence (IL-18BS) upstream of exon 1 of the murine IL-18 gene and three IL-18BSs in the promoter region of human IL-18 gene. Binding of Bcl6 in nuclear protein from resting RAW264 cells to murine IL-18BS was detected by gel retardation assay and chromatin immunoprecipitation assay. The binding activity was diminished gradually in RAW264 cells after LPS stimulation. However, the amount of Bcl6 protein in these cells was constant over the period examined, suggesting the functional modification of Bcl6 protein after stimulation. Furthermore, murine IL-18BS was required for Bcl6 to repress the expression of the luciferase reporter gene under control of the IL-18 promoter. Taken together, Bcl6 is a key regulator of IL-18 production by macrophages.

Direct Repression of prdm1 by Bcl-6 Inhibits Plasmacytic Differentiation

“…The Bcl-6 response element in intron 5 (BRE1) is conserved in the human gene and was shown to be bound by Bcl-6 both in vitro and in vivo. Our study adds prdm1 to the list of IL-5, IL-18, B7-1, and Bcl-6 itself that are direct targets of Bcl-6 (22)(23)(24)(25)(26). Our results are consistent with previous microarray studies which identified PRDM1 as a direct target of Bcl-6 repression (5).…”

Hypoxia-induced IL-18 Increases Hypoxia-inducible Factor-1α Expression through a Rac1-dependent NF-κB Pathway

“…As is shown in Figure 1E, prominent upregulation of promoter activity was observed upon the transfection of the P179 construct. The IL-18 promoter harbors several positive elements, including AP-1, NF-B, and ICSBP (Kim et al, 2000), and negative elements including bcl-6 (Takeda et al, 2003). Bcl-6, which is a transcriptional repressor for IL-18 gene expression via the binding of Ϫ2574 to Ϫ2565 bp of the IL-18 P1 promoter, was also increased under hypoxic conditions.…”

Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma

“…We used BCL6 mRNA and protein expression, and mutation and translocation data, to perform supervised analyses of the expression of BCL6 target genes 31,39,40 in the different subgroups of DLBCL. Target gene selection was described in the Materials and methods section and repression of the majority of the target genes was observed in all three subsets when the level of BCL6 expression was sufficiently high at both protein or mRNA level.…”