Synergistic anti-HSV effect of tumor necrosis factor alpha and interferon gamma in human corneal fibroblasts is associated with interferon beta induction.
HSV-1 (17) replicated to high titer in human corneal fibroblasts (> 10(8) PFU/10(5) cells) following infection at one PFU per 100 cells. Pretreatment of the cells for 24 h with 50 U/ml recombinant human tumor necrosis factor alpha (TNF-alpha) or 5 IU/ml of human interferon gamma (IFN-gamma) resulted in only modest reduction (2- to 19-fold) in virus yield. However, when the two cytokines were combined the antiviral effect was dramatically increased. There was > 1000-fold reduction in virus titer in 8 of 8 trials. In contrast, the combinations of 50 U/ml TNF-alpha with 5 IU/ml IFN-alpha or IFN-beta did not produce a synergistic effect. The pronounced synergistic antiviral activity of TNF-alpha+IFN-gamma could be demonstrated in fibroblast cultures from different donors, and HSV-2 as well as HSV-1 strains were inhibited. There was no evidence that dual cytokine treatment was toxic for uninfected or HSV-infected cells. Insight into the mechanism responsible for the synergistic effect was provided by the observation that TNF-alpha+IFN-gamma induced IFN-beta. In addition, anti-IFN-beta but not anti-IFN-alpha antibodies could reverse the antiviral effect, and reconstitution with IFN-beta could duplicate the phenomenon. We conclude that the combination of TNF-alpha and IFN-gamma at low concentrations can exert a powerful anti-herpes effect in human corneal fibroblasts which can be chiefly attributed to the induction of IFN-beta.
Chen
S H
SH
Department of Microbiology and Immunology, College of Medicine, University of South Alabama, Mobile 36688.
Oakes
J E
JE
Lausch
R N
RN
D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003315:Cornea / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D007371:Interferon-gamma