REGULATION OF THE IFN SYSTEM BY
Interferon regulatory factors 1 and 2 (IRF-1 and -2)
IRF-1 AND ITS FAMILY MEMBERS were originally identified as a transcriptional activator and repressor, respectively, of the interferon-b (IFN-b)
Although it was shown previously that IRF-1 can and of IFN-inducible genes. However, these factors indeed activate the IFN-a/b genes, it turned out that have since been shown to modulate not only the cellular this process is somewhat more complicated, requiring, response to IFNs and viral infection but also cell in addition to IRF-1 up-regulation, a posttranslational growth, susceptibility to transformation by oncogenes, signal elicited by virus infection or dsRNA (7). Moreinduction of apoptosis, and development of the T-cell over, gene knockout studies have revealed an IRF-1immune response. Furthermore, recent evidence sugindependent pathway of the IFN gene induction gests that deletion and/or inactivation of the IRF-1 gene (11,12). More recently, it has been demonstrated may be a critical step in the development of some huthat ISGF3, which was originally found in the context man hematopoietic neoplasms. Thus, IRF-1 appears to of IFN signalling (4), plays a crucial role in this be be involved infinitely in a wide spectrum of hostprocess (13). defense mechanisms.
However, IRF-1 has been demonstrated as essential for the antiviral response to IFNs. Both IRF-1 and p48 IRF TRANSCRIPTION FACTORS (in the context of ISGF3) seem to be crucial for the cells to establish the antiviral state against a variety IRF-1 and IRF-2 were originally identified as factors of viruses in response to IFNs (14). In contrast, the that bound to sequences found in the IFN-a and -b role of IRF-2 in IFN response still remains obscure, promoters (1,2). These two factors are highly homoloalthough it may serve as a negative regulator of the gous to one another in their amino-terminal regions, IFN response (2,10). the regions that confer DNA-binding specificity, and bind with similar affinities to common DNA sequence ANTI-ONCOGENIC AND ONCOGENIC elements, designated IRF-Es (2,3). The IRFs also share POTENTIALS OF IRFS homology in their DNA-binding regions with p48, the The growth of mouse NIH 3T3 cells can be arrested major DNA-binding component of a heterotrimeric in the G 0 (quiescent) phase of the cell cycle by culturing transcription factor complex, termed ISGF-3 (4). This in the absence of serum and then stimulated to proceed homology is functionally significant because the IRFs through the cell cycle in a synchronous manner by the and ISGF-3 bind to overlapping sequences in the prore-addition of serum. In cells arrested by serum starvamoters of many IFN-a/b-inducible genes (3). tion, IRF-1 mRNA expression is markedly elevated, but Gene transfection studies have shown that IRF-1 can following the re-addition of serum expression declines function as an activator, inducing transcription from 6-fold followed by a gradual increase prior to and durpromoters containing IRF-Es (2). In contrast, IRF-2 aning DNA synthesis. In contrast, IRF-2 mRNA levels tagonizes the function of IRF-1 by competing with it remain constant throughout the cell cycle (8). Thus, the for binding to the same sites in the promoter and possiratio of IRF-1:IRF-2 expression oscillates through the bly by repressing activators positioned nearby (5,6). cell cycle, with this ratio at its highest (i.e., high IRF-Both IRF-1 and IRF-2 mRNAs are expressed at low 1) in growth-arrested cells and its lowest (i.e., low IRFconstitutive levels in the cell, but the IRF-2 protein is 1) following growth stimulation. Several experiments more stable and thus accumulates to higher levels have demonstrated that alterations in IRF-1:IRF-2 ex-(half-lives of 8 hr vs. 30 min) (7,8). This behavior results pression levels can have significant consequences for in the relative repression of promoters under the concell growth. For example, ectopic overexpression of trol of the IRFs. However, IRF-1 can briefly usurp the IRF-1 strongly inhibits cell proliferation in several cell dominance of IRF-2 when cells are stimulated by virus, types (15,16). Conversely, overexpression of IRF-2 double-stranded RNA (dsRNA), IFNs, and/or by the cytokines TNF, interleukin (IL)-1, IL-6, prolactin, or LIF [(9), references in (10)]. These stimuli cause the tran-*