Regulation of IL-18 (IFN-gamma-inducing factor) gene expression.
IL-18 (also known as IFN-gamma-inducing factor), although structurally unrelated to IL-12, shares with it the role of activating NK cells and polarizing T cells toward Th1 cell function. To understand how the IL-18 gene (and consequently Th1 function) is regulated, we have determined the gene structure and investigated the mechanisms of transcriptional control and cell type expression. The mouse IL-18 gene comprises seven exons distributed over 26 kb. Exons 1 and 2 of this gene are 5'-noncoding exons. Promoter activity was detected upstream of these noncoding exons in two distinct regions. Both promoters are TATA-less and not G+C rich. The promoter activity located upstream of exon 2 was shown to act constitutively, while the activity located upstream of exon 1 was up-regulated in activated macrophage and T cell lines. IL-18 gene expression may be regulated in a wide range of cell types by the activities of these two distinct promoters. IL-18 is known to be synthesized as a precursor, pro-IL-18, and its maturation is controlled by IL-1beta-converting enzyme (ICE). We observed concordant expression of IL-18 and ICE mRNAs in a wide range of cell types, unlike the more restricted expression of IL-12 p40 mRNA. The widespread IL-18 mRNA distribution and the special relationship with ICE lead us to the hypothesis that IL-18 expression may be coupled with apoptotic processes involving activation of ICE or ICE-like proteinase.
Tone
M
M
Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
Thompson
S A
SA
Tone
Y
Y
Fairchild
P J
PJ
Waldmann
H
H
D000818:Animals; D001483:Base Sequence; D020170:Caspase 1; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D016207:Cytokines / Q000737:chemistry / Q000235:genetics*; D004622:Embryo, Mammalian; D005091:Exons; D005786:Gene Expression Regulation; D005796:Genes / Q000276:immunology*; D007375:Interleukin-1 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics; D020382:Interleukin-18; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D013234:Stem Cells; D014158:Transcription, Genetic / Q000276:immunology
D016207:Cytokines; D007375:Interleukin-1; D020382:Interleukin-18; D012333:RNA, Messenger; D018664:Interleukin-12; D003546:Cysteine Endopeptidases; D020170:Caspase 1