Part 2

Type 1 interferons (IFN-α/IFN-β) are a family of cytokines, which induce multiple cellular changes. The major biological responses of cells treated with interferons are the inhibition of viral replication in these cells and a decrease in cell-growth rate. During the last few years several steps of the molecular mechanism of the interferon-induced signaling pathway have been elucidated, but many aspects remain unclear (for recent reviews.)

Interferons interact with cells through specific cell surface receptors. The interaction of IFN-α/IFN-β with its proper receptor ultimately results in the induction of the expression of a group of IFN-α/IFN-β stimulated genes. IFN-α/IFN-β induced gene expression is directly regulated at the level of transcription. Transcriptional stimulation in response to interferon treatment is at least partially mediated by preexisting cellular proteins, which become activated in response to the signaling pathway. Recently, it has been shown that a cytoplasmic protein tyrosine kinase (tyk2) is involved in the latter process. In general, directly IFN-α/IFN-β stimulated genes isolated thus far are characterized by the presence of a cis-acting DNA sequence (interferon-stimulated response element, ISRE) in the promoter region. An ISRE consensus sequence AGTTTCNNTTTC(CT) has been deduced from elements present in the different IFN-a/IFN-p-regulated promoters. The ISRE specifically binds at least two transacting nuclear factors (or transcription-factor complexes) in a manner which correlates with transcriptional activation of the target genes.

One of the best characterized positive factors { interferon-stimulated-genefactor 2 (ISGF2) or interferon-regulatory factor 1 (IRF-1). In co-transfection experiments, ISGF2(IRF-1) can bind to an ISRE and induce transcription from a target promoter is rapidly induced upon treatment of cells with IFN-α/IFN-β, even without protein synthesis . Therefore, ISGF3 probably is the major transcription factor involved in the IFN-α/IFN-β signal transduction pathway. In the absence of IFN-α/IFN-β , ISGF3 is present in an inactive form in the cytoplasm.