1887

Abstract

Toll-like receptor 3 (TLR-3) and TLR-9 gene expression and interleukin 6 (IL-6) secretion were studied in corneal cells with components of herpes simplex virus (HSV). Human corneal epithelial cells (HCEs) and primary human corneal fibroblasts (HCRFs) were infected with live HSV or UV-inactivated HSV (UV-HSV), transfected with HSV DNA or treated with HSV–anti-HSV IgG immune complexes. Gene expression of TLR-3 and -9 was analysed by real-time PCR. Supernatants were assayed for IL-6 by ELISA. Incubation of HCEs and HCRFs with live HSV-1, UV-HSV and HSV DNA resulted in augmented TLR-3 and -9 gene expression and IL-6 release. Moreover, infected or transfected HCRFs released greater amounts of IL-6 than did HCEs. As virus is frequently in the form of neutralized virus immune complexes, the ability of these immune complexes to interact with TLRs and trigger IL-6 production was evaluated. Here, it is shown that HSV–anti-HSV IgG complexes were as potent as HSV DNA in their ability to induce IL-6. Treatment of HCRFs transfected with HSV DNA with the TLR-9-inhibitory oligomer iODN, anti-TLR-3 antibody or phosphatidylinositol 3-kinase inhibitor indicated that IL-6 release from HCRFs was mediated by TLR-3 and -9 gene expression. These results demonstrated that neutralized HSV immune complexes were as potent as HSV DNA in enhancing IL-6 release from corneal fibroblasts. These phenomena were mediated via augmented TLR-3 and -9 gene expression.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.81772-0
2006-08-01
2019-11-14
Loading full text...

Full text loading...

/deliver/fulltext/jgv/87/8/2161.html?itemId=/content/journal/jgv/10.1099/vir.0.81772-0&mimeType=html&fmt=ahah

References

  1. Ahmad-Nejad, P., Häcker, H., Rutz, M., Bauer, S., Vabulas, R. M. & Wagner, H. ( 2002; ). Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur J Immunol 32, 1958–1968.[CrossRef]
    [Google Scholar]
  2. Akira, S. & Takeda, K. ( 2004; ). Toll-like receptor signalling. Nat Rev Immunol 4, 499–511.[CrossRef]
    [Google Scholar]
  3. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. ( 2001; ). Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738.[CrossRef]
    [Google Scholar]
  4. Araki-Sasaki, K., Ohashi, Y., Sasabe, T., Hayashi, K., Watanabe, H., Tano, Y. & Handa, H. ( 1995; ). An SV40-immortalized human corneal epithelial cell line and its characterization. Invest Ophthalmol Vis Sci 36, 614–621.
    [Google Scholar]
  5. Biswas, P. S., Banerjee, K., Kinchington, P. R. & Rouse, B. T. ( 2006; ). Involvement of IL-6 in the paracrine production of VEGF in ocular HSV-1 infection. Exp Eye Res 82, 46–54.[CrossRef]
    [Google Scholar]
  6. Centifanto-Fitzgerald, Y. M., Yamaguchi, T., Kaufman, H. E., Tognon, M. & Roizman, B. ( 1982; ). Ocular disease pattern induced by herpes simplex virus is genetically determined by a specific region of viral DNA. J Exp Med 155, 475–489.[CrossRef]
    [Google Scholar]
  7. Doymaz, M. Z. & Rouse, B. T. ( 1992; ). Immunopathology of herpes simplex virus infections. Curr Top Microbiol Immunol 179, 121–136.
    [Google Scholar]
  8. Fenton, R. R., Molesworth-Kenyon, S., Oakes, J. E. & Lausch, R. N. ( 2002; ). Linkage of IL-6 with neutrophil chemoattractant expression in virus-induced ocular inflammation. Invest Ophthalmol Vis Sci 43, 737–743.
    [Google Scholar]
  9. Guillot, L., Le Goffic, R., Bloch, S., Escriou, N., Akira, S., Chignard, M. & Si-Tahar, M. ( 2005; ). Involvement of Toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J Biol Chem 280, 5571–5580.[CrossRef]
    [Google Scholar]
  10. Gursel, I., Gursel, M., Yamada, H., Ishii, K. J., Takeshita, F. & Klinman, D. M. ( 2003; ). Repetitive elements in mammalian telomeres suppress bacterial DNA-induced immune activation. J Immunol 171, 1393–1400.[CrossRef]
    [Google Scholar]
  11. Hemmi, H., Takeuchi, O., Kawai, T. & 8 other authors ( 2000; ). A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745.[CrossRef]
    [Google Scholar]
  12. Ishii, K. J., Takeshita, F., Gursel, I., Gursel, M., Conover, J., Nussenzweig, A. & Klinman, D. M. ( 2002; ). Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation. J Exp Med 196, 269–274.[CrossRef]
    [Google Scholar]
  13. Iwasaki, A. & Medzhitov, R. ( 2004; ). Toll-like receptor control of the adaptive immune responses. Nat Immunol 5, 987–995.[CrossRef]
    [Google Scholar]
  14. Karikó, K., Ni, H., Capodici, J., Lamphier, M. & Weissman, D. ( 2004; ). mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 279, 12542–12550.[CrossRef]
    [Google Scholar]
  15. Kaye, S. B., Baker, K., Bonshek, R., Maseruka, H., Grinfeld, E., Tullo, A., Easty, D. L. & Hart, C. A. ( 2000; ). Human herpesviruses in the cornea. Br J Ophthalmol 84, 563–571.[CrossRef]
    [Google Scholar]
  16. Krieg, A. M., Wu, T., Weeratna, R., Efler, S. M., Love-Homan, L., Yang L., Yi, A.-K., Short, D. & Davis, H. L. ( 1998; ). Sequence motifs in adenoviral DNA block immune activation by stimulatory CpG motifs. Proc Natl Acad Sci U S A 95, 12631–12636.[CrossRef]
    [Google Scholar]
  17. Krug, A., Luker, G. D., Barchet, W., Leib, D. A., Akira, S. & Colonna, M. ( 2004; ). Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 103, 1433–1437.
    [Google Scholar]
  18. Kurt-Jones, E. A., Chan, M., Zhou, S., Wang, J., Reed, G., Bronson, R., Arnold, M. M., Knipe, D. M. & Finberg, R. W. ( 2004; ). Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc Natl Acad Sci U S A 101, 1315–1320.[CrossRef]
    [Google Scholar]
  19. Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. ( 2003; ). Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 198, 513–520.[CrossRef]
    [Google Scholar]
  20. Lundberg, P., Welander, P., Han, X. & Cantin, E. ( 2003; ). Herpes simplex virus type 1 DNA is immunostimulatory in vitro and in vivo. J Virol 77, 11158–11169.[CrossRef]
    [Google Scholar]
  21. Maggs, D. J., Chang, E., Nasisse, M. P. & Mitchell, W. J. ( 1998; ). Persistence of herpes simplex virus type 1 DNA in chronic conjunctival and eyelid lesions of mice. J Virol 72, 9166–9172.
    [Google Scholar]
  22. Marsters, S. A., Ayres, T. M., Skubatch, M., Gray, C. L., Rothe, M. & Ashkenazi, A. ( 1997; ). Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-κB and AP-1. J Biol Chem 272, 14029–14032.[CrossRef]
    [Google Scholar]
  23. Matsumoto, M., Kikkawa, S., Kohase, M., Miyake, K. & Seya, T. ( 2002; ). Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem Biophys Res Commun 293, 1364–1369.[CrossRef]
    [Google Scholar]
  24. Means, T. K., Latz, E., Hayashi, F., Murali, M. R., Golenbock, D. T. & Luster, A. D. ( 2005; ). Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 115, 407–417.[CrossRef]
    [Google Scholar]
  25. Meyers, R. L. & Chitjian, P. A. ( 1976; ). Immunology of herpesvirus infection: immunity to herpes simplex virus in eye infections. Surv Ophthalmol 21, 194–204.[CrossRef]
    [Google Scholar]
  26. Meyers, R. L. & Pettit, T. H. ( 1973; ). The pathogenesis of corneal inflammation due to herpes simplex virus. I. Corneal hypersensitivity in the rabbit. J Immunol 111, 1031–1042.
    [Google Scholar]
  27. Meyers-Elliot, R. H., Pettit, T. H. & Maxwell, W. A. ( 1980; ). Viral antigens in the immune ring of herpes simplex stromal keratitis. Arch Ophthalmol 98, 897–904.[CrossRef]
    [Google Scholar]
  28. Mitchell, W. J., Gressens, P., Martin, J. R. & DeSanto, R. ( 1994; ). Herpes simplex virus type 1 DNA persistence, progressive disease and transgenic immediate early gene promoter activity in chronic corneal infections in mice. J Gen Virol 75, 1201–1210.[CrossRef]
    [Google Scholar]
  29. Montgomery, R. I., Warner, M. S., Lum, B. J. & Spear, P. G. ( 1996; ). Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87, 427–436.[CrossRef]
    [Google Scholar]
  30. Netea, M. G., Van der Meer, J. W. M. & Kullberg, B.-J. ( 2004; ). Toll-like receptors as an escape mechanism from the host defense. Trends Microbiol 12, 484–488.[CrossRef]
    [Google Scholar]
  31. Niemialtowski, M. G. & Rouse, B. T. ( 1992; ). Predominance of Th1 cells in ocular tissues during herpetic stromal keratitis. J Immunol 149, 3035–3039.
    [Google Scholar]
  32. Sarkar, S. N., Peters, K. L., Elco, C. P., Sakamoto, S., Pal, S. & Sen, G. C. ( 2004; ). Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double stranded RNA signalling. Nat Struct Mol Biol 11, 1060–1067.[CrossRef]
    [Google Scholar]
  33. Sen, G. C. & Sarkar, S. N. ( 2005; ). Transcriptional signaling by double-stranded RNA: role of TLR3. Cytokine Growth Factor Rev 16, 1–14.[CrossRef]
    [Google Scholar]
  34. Smith, J. W., Jachimowicz, J. R. & Bingham, E. L. ( 1986; ). Binding and internalization of herpes simplex virus-antibody complexes by polymorphonuclear leukocytes. J Med Virol 20, 151–163.[CrossRef]
    [Google Scholar]
  35. Streilein, J. W., Dana, M. R. & Ksander, B. R. ( 1997; ). Immunity causing blindness: five different paths to herpes stromal keratitis. Immunol Today 18, 443–449.[CrossRef]
    [Google Scholar]
  36. Sudesh, S. & Laibson, P. R. ( 1999; ). The impact of the herpetic eye disease studies on the management of herpes simplex virus ocular infections. Curr Opin Ophthalmol 10, 230–233.[CrossRef]
    [Google Scholar]
  37. Takeda, K., Kaisho, T. & Akira, S. ( 2003; ). Toll-like receptors. Annu Rev Immunol 21, 335–376.[CrossRef]
    [Google Scholar]
  38. Tang, Q., Chen, W. & Hendricks, R. L. ( 1997; ). Proinflammatory functions of IL-2 in herpes simplex virus corneal infection. J Immunol 158, 1275–1283.
    [Google Scholar]
  39. Thomas, J. & Rouse, B. T. ( 1997; ). Immunopathogenesis of herpetic ocular disease. Immunol Res 16, 375–386.[CrossRef]
    [Google Scholar]
  40. Tian, B., Bevilacqua, P. C., Diegelman-Parente, A. & Mathews, M. B. ( 2004; ). The double-stranded-RNA-binding motif: interference and much more. Nat Rev Mol Cell Biol 5, 1013–1023.[CrossRef]
    [Google Scholar]
  41. Ueta, M., Hamuro, J., Kiyono, H. & Kinoshita, S. ( 2005; ). Triggering of TLR3 by polyI : C in human corneal epithelial cells to induce inflammatory cytokines. Biochem Biophys Res Commun 331, 285–294.[CrossRef]
    [Google Scholar]
  42. Verjans, G. M., Remeijer, L., van Binnendijk, R. S., Cornelissen, J. G., Volker-Dieben, H. J., Baarsma, S. G. & & Osterhaus, A. D. M. E. ( 1998; ). Identification and characterization of herpes simplex virus-specific CD4+ T cells in corneas of herpetic stromal keratitis patients. J Infect Dis 177, 484–488.[CrossRef]
    [Google Scholar]
  43. Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. ( 1994; ). A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269, 5241–5248.
    [Google Scholar]
  44. Wander, A. H., Centifanto, Y. M. & Kaufman, H. E. ( 1980; ). Strain specificity of clinical isolates of herpes simplex virus. Arch Ophthalmol 98, 1458–1461.[CrossRef]
    [Google Scholar]
  45. Wilhelmus, K. R., Gee, L. Hauck, W. W. & other authors ( 1994; ). Herpetic eye disease study: a controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 101, 1883–1896.[CrossRef]
    [Google Scholar]
  46. Xu, F., Schillinger, J. A., Sternberg, M. R., Johnson, R. E., Lee, F. K., Nahmias, A. J. & Markowitz, L. E. ( 2002; ). Seroprevalence and coinfection with herpes simplex virus type 1 and type 2 in the United States, 1988-1994. J Infect Dis 185, 1019–1024.[CrossRef]
    [Google Scholar]
  47. Xu, M., Lepisto, A. J. & Hendricks, R. L. ( 2004; ). CD154 signaling regulates the Th1 response to herpes simplex virus-1 and inflammation in infected corneas. J Immunol 173, 1232–1239.[CrossRef]
    [Google Scholar]
  48. Yamamoto, M., Sato, S., Mori, K., Hoshino, K., Takeuchi, O., Takeda, K. & Akira, S. ( 2002; ). Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J Immunol 169, 6668–6672.[CrossRef]
    [Google Scholar]
  49. Zheng, M., Klinman, D. M., Gierynska, M. & Rouse, B. T. ( 2002; ). DNA containing CpG motifs induces angiogenesis. Proc Natl Acad Sci U S A 99, 8944–8949.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.81772-0
Loading
/content/journal/jgv/10.1099/vir.0.81772-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error