Induction of genes involved in cell cycle progression by interleukin-4

Interleukin-4 (IL-4) can elicit diverse cellular responses, including differentiation, fusion, and proliferation, and these are all critical to establishment of an effective immune response. In this report, we provide evidence that IL-4 induces the proliferation of T lymphocytes with the coordinate transcriptional induction of the cell cycle regulatory genes encoding Cdc25A and the minichromosome maintenance (MCM) family. This specific gene induction appears to be due to activation of the signal transducer and activator of transcription, Stat6, and in part to phosphatidylinositol 3-kinase (PI3K). The function of another family of transcription factors, E2F, is known to induce cell cycle-regulated gene expression by binding to specific DNA target sites. We demonstrate that IL-4-activated Stat6 dimers can bind to a subset of E2F target sites and stimulate gene expression by binding to these DNA elements. Our results support a role for the Stat6 signal pathway in regulating a subset of E2F-responsive genes. In addition, activation of PI3K may play a complementary role in the induction of cell cycle-regulated genes in response to IL-4.