Activation of the transcription factor interferon regulatory factor-3 (IRF-3) is an essential event in the innate immune response to viral infection. To understand the contribution of IRF-3 to host defense, we used a systems biology approach to analyze global gene expression dependent on IRF-3. Comparison of expression profiles in cells from IRF-3 knockout animals or wild-type siblings following viral infection revealed three sets of induced genes, those that are strictly dependent on IRF-3, augmented with IRF-3, or not responsive to IRF-3. Products of identified IRF-3 target genes are involved in innate or acquired immunity, or in the regulation of cell cycle, apoptosis and proliferation. These results reveal the global effects of one transcription factor in the immune response and provide information to evaluate the integrated response to viral infection.
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.
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