The ST2 gene encodes receptor-like molecules that are very similar to the type I interleukin-1 receptor. Two distinct types of the ST2 gene products, ST2 (a soluble secreted form) and ST2L (a transmembrane form) are produced by alternative splicing. Here we demonstrate that the human ST2 gene has two alternative promoters followed by distinct noncoding first exons, which are located more than 8 kb apart and are spliced to the common exon 2 containing the translation initiation site. Within 1001 bp upstream of the transcription initiation site of the cloned distal promoter, there are four GATA-1. The main promoter used for the expression of the ST2 gene in UT-7, a human leukaemic cell line, is distinct from that in TM12, a human fibroblastic cell line. Although UT-7 cells use both distal and proximal promoters, the distal promoter is used dominantly for expression of both ST2 and ST2L mRNA. On the other hand, almost all transcription in TM12 cells starts from the proximal promoter. These results contrast with those of former studies on the rat system, in which ST2 and ST2L mRNA were generated by use of the proximal and distal promoters, respectively. Furthermore, UT-7 cells use multiple transcription initiation sites in both the proximal and distal promoters, whereas the transcription of the ST2 gene in TM12 cells starts at a unique site. Intriguingly, these results suggest that ST2 and ST2L proteins have distinct functions in different cells within different biological systems, such as those of growth control, differentiation and immunological responses.Keywords: immunoglobulin superfamily; interleukin-1 receptor-related protein; orphan receptor; promoter usage; ST2 gene.The ST2 gene, also designated as T1, Fit-1 or DER4, was cloned as one of the primary response genes in the G 0 /G 1 transitional state of BALB/c-3T3 cells [1], a H-ras oncogeneresponsive gene [2], a Fos-responsive gene [3], and a delayed early serum response gene [4]. Subsequently, ST2L cDNA, encoding a membrane-bound protein the extracellular domain of which is almost identical to the ST2 protein, was cloned [5]. The mRNAs of ST2 and ST2L were produced by alternative 3 H splicing of the primary transcript of the ST2 gene [6]. Based on this discovery of the ST2 gene and its expression in fibroblastic cell lines, our previous studies focused on the function of the ST2 gene in growth control.On the other hand, structural analysis of the ST2 cDNA revealed that the ST2 protein was remarkably similar to the members of the immunoglobulin superfamily, especially to the extracellular portion of the mouse interleukin-1 receptor (IL-1R) [1], and the ST2L protein showed a striking overall similarity to the mouse type I interleukin (IL)-1 receptor (IL-1RI) [5]. Furthermore, the genes encoding ST2 and the two IL-1 receptors, IL-1RI and IL-1RII, were tightly linked on mouse chromosome 1 [7] and human chromosome 2 [8]. The human ST2 gene was assigned to chromosome 2q11.2 [9]. However, IL-1a, b, and receptor antagonist did not bind to the ST2L protein, suggesti...