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A Proximal B Site in the IL-23 p19 Promoter Is Responsible for RelA- and c-Rel-Dependent Transcription

Setsuko Mise-Omata^*, Etsushi Kuroda, Junko Niikura^*, Uki Yamashita, Yuichi Obata^* and Takahiro S. Doi^1,*

^* Technology and Development Team for BioSignal Program, Subteam for BioSignal Integration, RIKEN BioResource Center, RIKEN Tsukuba Institute, Tsukuba, Japan; and Department of Immunology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan

IL-23 is a heterodimeric cytokine composed of a unique p19 subunit and a common p40 subunit is shared with IL-12. IL-23 promotes the inflammatory response by inducing the expansion of CD4⁺ cells producing IL-17. The regulation of p19 gene expression has been less studied than that of p40 subunit expression, which in macrophages is well known to be dependent on NF-B. To clarify the role of NF-B in expression of the p19 gene, we analyzed mRNA levels in NF-B-deficient macrophages. As reported to occur in dendritic cells, p19 expression was dramatically reduced in c-rel-deficient macrophages. Moreover, we found that p19 expression was halved in rela-deficient macrophages, but it was enhanced in p52-deficient macrophages. The p19 promoter contains three putative B sites, located at nt –642 to –632 (B–642), nt –513 to –503 (B–513), and nt –105 to –96 (B–105), between the transcription start site and –937 bp upstream in the p19 promoter region. Although EMSA analysis indicated that both B–105 and B–642, but not B–513, bound to NF-B in vitro, luciferase-based reporter assays showed that the most proximal B site, B–105, was uniquely indispensable to the induction of p19 transcription. Chromatin immunoprecipitation demonstrated in vivo association of RelA, c-Rel, and p50 with B–105 of the p19 promoter. These results provide the evidence that the association of RelA and c-Rel with the proximal B site in the p19 promoter is required to induce of p19 expression.

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¹ Address correspondence and reprint requests to Dr. Takahiro S. Doi, Technology and Development Team for BioSignal Program, Subteam for BioSignal Integration, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Japan. E-mail address: bri{at}brc.riken.jp

² Abbreviations used in this paper: BMDM, bone marrow-derived macrophages; HPRT, hypoxanthine-guanine phosphoribosyltransferase; ChIP, chromatin immunoprecipitation.