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 an d polarizing T cells toward Th1 cell function. To understand how the I L-18 gene (and consequently Th1 function) is regulated, we have determ ined the gene structure and investigated the mechanisms of transcripti onal 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 nonc oding exons in two distinct regions. Both promoters are TATA-less and not G+C rich. The promoter activity located upstream of exon 2 was sho wn to act constitutively, while the activity located upstream of exon 1 was up-regulated in activated macrophage and T cell lines. IL-18 gen e expression may be regulated in a wide range of cell types by the act ivities of these two distinct promoters. IL-18 is known to be synthesi zed as a precursor, pro-IL-18, and its maturation is controlled by IL- 1 beta-converting enzyme (ICE). We observed concordant expression of I L-18 and ICE mRNAs in a wide range of cell types, unlike the more rest ricted expression of IL-l 2 p40 mRNA. The widespread IL-18 mRNA distri bution and the special relationship with ICE lead us to the hypothesis that IL-18 expression may be coupled with apoptotic processes involvi ng activation of ICE or ICE-like proteinase.