SYNERGISTIC ANTI-HERPES EFFECT OF TNF-ALPHA AND IFN-GAMMA IN HUMAN CORNEAL EPITHELIAL-CELLS COMPARED WITH THAT IN CORNEAL FIBROBLASTS

In this study we compared how effectively the proinflammatory cytokines TNF-alpha and IFN-gamma 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-alpha (50 U/ml) and IFN-gamma (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-beta because antibody to this cytokine but not TFN-alpha abrogated synergism. The more modest synergistic effect in epithelial cells was associated with a greater than or equal to 4-fold reduction in the synthesis of IFN-beta protein and mRNA, and decreased responsiveness of these cells to the antiviral effect of IFN-beta. We conclude that the combination of TNF-alpha and IFN-gamma 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-beta induced and the target cell responsiveness to the antiviral action of this cytokine.