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.

[1]  S. Mittnacht,et al.  Interferon treatment inhibits onset of herpes simplex virus immediate-early transcription. , 1988, Virology.

[2]  T. K. Hughes,et al.  Synergy of antiviral actions of TNF and IFN-γ: Evidence for a major role of TNF-induced IFN-β , 1988 .

[3]  J. Oakes,et al.  Evidence endogenous interferon production contributed to the lack of ocular virulence of an HSV intertypic recombinant. , 1991, Current eye research.

[4]  R. Weiss.  Synergistic antiviral activities of acyclovir and recombinant human leukocyte (alpha) interferon on feline herpesvirus replication. , 1989, American journal of veterinary research.

[5]  V. Raju,et al.  Differences in natural and recombinant interferon for herpes keratitis in two animal models. , 1984, Investigative ophthalmology & visual science.

[6]  C. Dieffenbach,et al.  Beta interferon subtype 1 induction by tumor necrosis factor , 1989, Molecular and cellular biology.

[7]  B. Aggarwal,et al.  Characterization of receptors for human tumour necrosis factor and their regulation by γ-interferon , 1985, Nature.

[8]  L. Smith,et al.  Quantitation of purified monoclonal antibody needed to prevent HSV-1 induced stromal keratitis in mice. , 1989, Current eye research.

[9]  T. Tumpey,et al.  Endogenously produced interferon alpha protects mice from herpes simplex virus type 1 corneal disease. , 1991, The Journal of general virology.

[10]  L. Old,et al.  Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Brinton,et al.  Comparative therapeutic efficacy of recombinant interferons-alpha, -beta, and -gamma against alphatogavirus, bunyavirus, flavivirus, and herpesvirus infections. , 1990, Journal of interferon research.

[12]  D. Wallach,et al.  Increase of vulnerability to lymphotoxin in cells infected by vesicular stomatitis virus and its further augmentation by interferon. , 1985, Cellular immunology.

[13]  B. Beutler,et al.  The biology of cachectin/TNF--a primary mediator of the host response. , 1989, Annual review of immunology.

[14]  D. Falke,et al.  In vivo protective effect of tumour necrosis factor alpha against experimental infection with herpes simplex virus type 1. , 1991, The Journal of general virology.

[15]  B. Aggarwal,et al.  Interrelationships of human interferon-gamma with lymphotoxin and monocyte cytotoxin , 1984, The Journal of experimental medicine.

[16]  Marian C. Horzinek,et al.  Tumour necrosis factor α, interferon γ and interferon β exert antiviral activity in nervous tissue cells , 1991 .

[17]  J. Oakes,et al.  Ocular avirulence of a herpes simplex virus type 1 strain is associated with heightened sensitivity to alpha/beta interferon , 1990, Journal of virology.

[18]  G. Nabel,et al.  Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Koff Wc,et al.  Human tumor necrosis factor-alpha kills herpesvirus-infected but not normal cells. , 1986 .

[20]  S. Mittnacht,et al.  Different effects of IFNγ and IFNα/β on “immediate early” gene expression of HSV-1 , 1990 .

[21]  C. Cubitt,et al.  IL-8 gene expression in cultures of human corneal epithelial cells and keratocytes. , 1993, Investigative ophthalmology & visual science.

[22]  G. Wong,et al.  Tumour necrosis factors α and β inhibit virus replication and synergize with interferons , 1986, Nature.

[23]  P. Asbell,et al.  The response of Langerhans cells in the cornea to herpetic keratitis. , 1987, Current eye research.

[24]  H. Staats,et al.  Effective antibody therapy in herpes simplex virus ocular infection. Characterization of recipient immune response. , 1990, Intervirology.

[25]  S. Mittnacht,et al.  Antiviral effects of recombinant tumour necrosis factor in vitro , 1986, Nature.

[26]  Luis Carrasco,et al.  Mechanism of inhibition of HSV-1 replication by tumor necrosis factor and interferon gamma. , 1991, Virology.

[27]  C. Chan,et al.  Identification of the lymphokines, interferon-gamma and interleukin-2, in inflammatory eye diseases. , 1988, Investigative ophthalmology & visual science.

[28]  D. Goeddel,et al.  Human tumor necrosis factor. Production, purification, and characterization. , 1985, The Journal of biological chemistry.

[29]  S. Baron,et al.  Nondetectable levels of interferon gamma is a critical host defense during the first day of herpes simplex virus infection. , 1987, Microbial pathogenesis.

[30]  G. Hensel,et al.  Protein kinase C-independent activation of nuclear factor kappa B by tumor necrosis factor. , 1990, The Journal of biological chemistry.

[31]  T. Taniguchi,et al.  Induction of the transcription factor IRF-1 and interferon-beta mRNAs by cytokines and activators of second-messenger pathways. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Ito,et al.  Antiviral effects of recombinant human tumor necrosis factor. , 1987, Lymphokine research.

[33]  B. Williams,et al.  Transcriptional regulation of interferon-stimulated genes. , 1991, European journal of biochemistry.

[34]  H. Kamiya,et al.  Effects of tumor necrosis factor alpha on replication of varicella-zoster virus. , 1991, Antiviral research.

[35]  J. Larrick,et al.  Journal of Leukocyte Biology 45:429-433 (1989) Activated Langerhans Cells Release Tumor Necrosis Factor , 2022 .

[36]  J. Vilček,et al.  Production of High-Titered Interferon in Cultures of Human Diploid Cells , 1972, Antimicrobial Agents and Chemotherapy.