In this study we compared how effectively the proinflammatory cytokines TNF-α and IFN-β could inhibit HSV-1 replication in human corneal tissue fragments and monolayers of epithelial cells and fibroblasts derived from intact corneas, and investigated the mechanism responsible for the inhibition. Pretreatment of corneal tissue or cells derived therefrom with TNF-α (50 U/ml) and IFN-γ (5 IU/ml) consistently induced a synergistic antiviral effect. Inhibition of HSV-1 growth was most evident in fibroblasts (> 1000-fold reduction) and less apparent (7-25-fold reduction) when epithelial cells were the target. Virus suppression was correlated with the induction of IFN-β because antibody to this cytokine but not IFN-α abrogated synergism. The more modest synergistic effect in epithelial cells was associated with a ≥ 4-fold reduction in the synthesis of IFN-β protein and mRNA, and decreased responsiveness of these cells to the antiviral effect of IFN-β. We conclude that the combination of TNF-α and IFN-γ induces a synergistic antiviral effect in corneal cells. The degree of synergism observed varies with the corneal cell type, and is correlated with the amount of IFN-β induced and the target cell responsiveness to the antiviral action of this cytokine.
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