Synergistic interaction between interferon-alpha and interferon-gamma through induced synthesis of one subunit of the transcription factor ISGF3.

Abstract

Interferon‐alpha (IFN alpha) and interferon‐gamma (IFN gamma) each induce in susceptible target cells a state of resistance to viral replication and reduced cellular proliferation, presumably through different mechanisms: these two polypeptides are unrelated by primary sequence and act through distinct cell‐surface receptors to induce expression of largely non‐overlapping sets of genes. However, acting in concert, they can produce synergistic interactions leading to mutual reinforcement of the physiological response. In HeLa cells, this synergistic response was initiated by cooperative induction of IFN alpha stimulated genes (ISGs). These normally quiescent genes were rapidly induced to high rates of transcription following exposure of cells to IFN alpha. Although they were only negligibly responsive to IFN gamma, combined treatment of cells with IFN gamma followed by IFN alpha resulted in an approximately 10‐fold increase in ISG transcription. ISG transcription is dependent upon ISGF3, a positive transcription factor specific for a cis‐acting regulatory element in ISG promoters. IFN gamma treatment induced increased synthesis of latent ISGF3, which was subsequently activated in response to IFN alpha to form approximately 10‐fold higher levels than detected in cells treated with IFN alpha alone. ISGF3 is composed of two distinct polypeptide components, synthesis of one of which was induced by IFN gamma, increasing its cellular abundance from limiting concentrations to a level which allowed formation of at least 10 times as much active ISGF3. Cell lines vary in their constitutive levels of the inducible component of ISGF3 and in the ability of IFNs to increase its synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Differentiation of Monocytes to Macrophages Switches theMycobacterium tuberculosisEffect on HIV-1 Replication from Stimulation to Inhibition: Modulation of Interferon Response and CCAAT/Enhancer Binding Protein β Expression

“…Regulation of the abundance of IRF-9 is an important mechanism for modulating IFN responsiveness (59). Further support for this conclusion comes from the observations that induction of ISGF-3 in undifferentiated monocytic cell lines is delayed and requires protein synthesis (60), while cells differentiated with PMA or all-trans-retinoic acid have increased levels of IRF-9 and exhibit rapid activation of ISGF-3 after IFN stimulation without the need for protein synthesis (38,39).…”

Expression regulation of zebrafish interferon regulatory factor 9 by promoter analysis

“…IRF9 is also known as ISGF3c, since it is first characterized as one IFNc-inducible component of ISGF3 (Levy et al, 1989). Therefore, pretreatment of mammalian cells with IFNc followed by IFNa results in a synergistically antiviral action of type I IFN and type II IFN (Levy et al, 1990;Lewis et al, 1989), since IFNc pretreatment can upregulate the expression of IRF9 that in turn augments IFNa-triggered signaling (Levy et al, 1990).…”

Essential and non‐redundant roles of p48 (ISGF3γ) and IRF‐1 in both type I and type II interferon responses, as revealed by gene targeting studies

“…the IFN-inducible genes (reviewed in Weissmann & Weber 1986;De Maeyer & De Maeyer-Guignard 1988;Vilček 1990;Sen & Ranshoff 1993;Darnell et al 1994). It has been well established that a heterotrimeric transcription factor complex, termed ISGF3, which consists of Stat1 / , Stat2 and p48, is formed upon type I IFN stimulation (Levy et al 1988(Levy et al , 1989(Levy et al , 1990David & Larner 1992;Fu et al 1992;Schindler et al 1992a,b;Veals et al 1992), and binds to the ISRE whose consensus sequence is A / G NGAAANN-GAAACT (Darnell et al 1994). In fact, ISREs can be found in the promoters of various IFN-inducible genes.…”