Cytokines

Cells respond to external stimuli with rapid and specific biological changes that can lead to proliferation, growth inhibition, differentiation, or cellular suicide. Polypeptide hormones (cytokines) can elicit these rapid physiological responses by binding to cell surface receptors and subsequently transmitting a signal to the nucleus that activates the transcription of a specific set of genes.

The signal transduction pathway of one class of cytokines initiates with the activation of tyrosine kinases of the Janus kinase (JAK) family. JAKs are associated with the cytoplasmic domains of cytokine transmembrane receptors. Following activation they phosphorylate latent cytoplasmic transcription factors that are members of the family of signal transducers and activators of transcription (STATs). Tyrosine phosphorylation of the STATs promotes the formation of homomeric or heteromeric protein complexes that translocate to the nucleus, bind to specific DNA target sites in the promoters of induced genes, and stimulate gene transcription.

Many cytokines that use JAK/STAT signal pathways function to enhance native and acquired immunity. Our ongoing studies with interferons, interleukin-2, interleukin-4, interleukin-6, and prolactin characterize the diverse physiological effects of cytokines, the molecular interactions that specify distinct STAT activation, the cytoplasmic/ nuclear localization of the STATs, the effect of oncoproteins on the STATs, and the role of JAK/STAT pathway in Drosophila development.

Viral Defense

The innate immune response to viral infection requires the expression of new genes that function in host survival. During viral infection with DNA or RNA viruses, viral dsRNA is generated by transcription and/or replication. This dsRNA is a potent intracellular signal that stimulates the defense response of the cell. One of the signal transduction pathways activated by dsRNA leads to the transcriptional induction of type I interferon genes. Interferons are cytokines that have the unique abilty to confer resistance to viral infections, inhibit the growth of normal and tumorigenic cells, and induce the differentiation and activation of a variety of immune cells. Our investigations have led to the discovery of another primary defense response of the cell that is stimulated by dsRNA and is independent of interferon. DsRNA activates a latent transcription factor, designated Interferon Regulatory Factor-3(IRF-3) that directly induces a subset of interferon stimulated genes. IRF-3 resides in the cytoplasm until it is specifically phosphorylated and then it translocates to the nucleus. Kinases recently identified that phosphorylate IRF-3 include NAK/TBP and IKKe.

Current studies on the IRF-3 defense pathway include analysis of the kinases that are activated by viral dsRNA to phosphorylate IRF-3, characterization of mechanisms that control nuclear-cytoplasmic localization, identification of genes that are activated specifically by IRF-3, and determination of the physiological effects of IRF-3 activation.