Regulation of human IL-18 gene expression: interaction of PU.1 with GC-box binding protein is involved in human IL-18 expression in myeloid cells.
Interleukin-18 (IL-18) is a pro-inflammatory cytokine which participates in host defense against a variety of infections as well as in chronic inflammation including autoimmune diseases. However, little is known about human IL-18 regulation at the gene level. We have previously demonstrated that sodium butyrate, a bacterial fermentation product, induces IL-18 production via the proximal region of the promoter. In this study we investigated the molecular mechanisms for basal and sodium butyrate-induced expression of IL-18 in human myeloid cells. Two regulatory regions, a consensus binding site for PU.1 and a GC-rich region, are required for basal IL-18 promoter activity in human myeloid cells. PU.1 bound to the PU.1 consensus binding site in electrophoretic mobility shift assays, and overexpression of PU.1 led to activation of the IL-18 promoter through this site. Mutation analysis revealed that the GC-rich region, but not PU.1 site, participates in sodium butyrate-induced transactivation. Furthermore, DNA pull-down experiments and the critical spacing of the two binding sites suggest that formation of a protein complex involving both cis elements and the respective binding proteins might be crucial for human IL-18 expression.
Koyama
Noriko
N
Department of Hematology, Johann Wolfgang Goethe University, Frankfurt, Germany.
Hoelzer
Dieter
D
Department of Hematology, Johann Wolfgang Goethe University, Frankfurt, Germany.
Ottmann
Oliver G
OG
Department of Hematology, Johann Wolfgang Goethe University, Frankfurt, Germany.
D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020862:GC Rich Sequence; D005786:Gene Expression Regulation; D006801:Humans; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics*; D022423:Myeloid Cells / Q000276:immunology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D020298:U937 Cells; D000099232:Proto-Oncogene Protein Spi-1
D004247:DNA; D004268:DNA-Binding Proteins; D020382:Interleukin-18; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1