The Antiviral Response to Gamma Interferon

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Abstract
A role for alpha/beta interferon (IFN-α/β) in the IFN-γ antiviral response has long been suggested. Accordingly, possible roles for autocrine or double-stranded-RNA (dsRNA)-induced IFN-α/β in the IFN-γ response were investigated. Use was made of wild-type and a variety of mutant human fibrosarcoma cell lines, including mutant U5A cells, which lack a functional IFN-α/β receptor and hence an IFN-α/β response. IFN-γ did not induce detectable levels of IFN-α/β in any of the cell lines, nor was the IFN-γ response per se dependent on autocrine IFN-α/β. On the other hand, a number of responses to dsRNA [poly(I) · poly(C)] and encephalomyocarditis virus were greatly enhanced by IFN-γ pretreatment (priming) of wild-type cells or of mutant cells lacking an IFN-α/β response; these include the primary induction of dsRNA-inducible mRNAs, including IFN-β mRNA, and, to a lesser extent, the dsRNA-mediated activation of the p38 mitogen-activated protein (MAP) kinase(s). IFN-γ priming of mRNA induction by dsRNA is dependent on JAK1 and shows biphasic kinetics, with an initial rapid (<30-min) response being followed by a more substantial effect on overnight incubation. The IFN-γ-primed dsRNA responses appear to be subject to modulation through the p38, phosphatidylinositol 3-kinase, and ERK1/ERK2 MAP kinase pathways. It can be concluded that despite efficient priming of IFN-β production, the IFN-α/β pathways play no significant role in the primary IFN-γ antiviral response in these cell-virus systems. The observed IFN-γ priming of dsRNA responses, on the other hand, will likely play a significant role in combating virus infection in vivo.