Essential roles of c-Rel in TLR-induced IL-23 p19 gene expression in dendritic cells.
IL-23 plays crucial roles in both immunity against pathogens and autoimmunity against self. Although it is well recognized that IL-23 expression is restricted to the myeloid lineage and is tightly regulated at the transcriptional level, the nature of transcription factors required for IL-23 expression is poorly understood. We report, in this study, that murine dendritic cells deficient in c-Rel, a member of the NF-kappaB family, are severely compromised in their ability to transcribe the p19 gene, one of the two genes that encode the IL-23 protein. The p19 gene promoter contains three putative NF-kappaB binding sites, two of which can effectively bind c-Rel as determined by chromatin immunoprecipitation and EMSA. Unexpectedly, mutation of either of these two c-Rel binding sites completely abolished the p19 promoter activity induced by five TLRs (2, 3, 4, 6, and 9) and four members of the NF-kappaB family (c-Rel, p65, p100, and p105). Based on these observations, we conclude that c-Rel controls IL-23 p19 gene expression through two kappaB sites in the p19 promoter, and propose a c-Rel-dependent enhanceosome model for p19 gene activation.
Carmody
Ruaidhrí J
RJ
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ruan
Qingguo
Q
Liou
Hsiou-Chi
HC
Chen
Youhai H
YH
D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000276:immunology*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D053760:Interleukin-23 Subunit p19 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists; D015533:Transcriptional Activation
D053760:Interleukin-23 Subunit p19; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D051193:Toll-Like Receptors