Antimitogenic and mitogenic actions of interleukin-1 in diverse cell types are associated with induction of gro gene expression

Interleukin-1 (IL-1) is an antiproliferative factor for growing human melanoma A375-C6 cells. To define the molecular basis for the action of IL-1, we set out to identify early genes induced by the cytokine in the absence of de novo protein synthesis. cDNA libraries were constructed from A375-C6 cells that were exposed or unexposed to IL-1 plus cycloheximide. Subtractive hybridization was used to prepare a library that was enriched for IL-1-induced clones. Two of these clones were shown by Northern analysis to represent IL-1-inducible genes. Nucleotide sequencing identified these genes as gro/melanoma growth stimulatory activity, which encodes a cell secretory product, and c-jun, which encodes a transcription factor. IL-1 caused persistent steady state elevation of gro mRNA but only transient induction of c-jun. Northern analysis using gene probes for the transcription factors c-fos and Egr-1 revealed that IL-1 induced c-fos but not Egr-1 expression in these cells. This indicates that differential early gene expression characterizes the growth-inhibitory action of IL-1. In contrast, serum, which is mitogenic for these cells, induces c-jun, c-fos, and Egr-1, but not gro expression. These data imply that in A375-C6 cells, both growth-inhibitory and stimulatory signals can channel their action through c-fos and c-jun genes. As gro induction was specifically associated with the antimitogenic action of IL-1, we studied the effect of the cytokine on gro gene expression in other types of cells. IL-1 was mitogenic for human glioblastoma and monkey kidney epithelial cells and induced gro whereas other mitogens did not. Thus, IL-1 can induce gro gene expression in diverse cell types, whether it acts to stimulate or inhibit proliferation. Like other cytokines gro may play diverse cell-specific roles in growth control.