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K. Hayashi, L. C. Hooper, B. Detrick, J. J. Hooks; HSV-IgG(Immune-Complex:IC) and HSV DNA Elicit Angiogenic VEGF in Corneal Fibroblasts and Monocytes, While MMP-9 Is Produced Only in Monocytes. Invest. Ophthalmol. Vis. Sci. 2007;48(13):731.
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In the herpetic stromal keratitis (HSK), viral DNA and IC are present in the cornea and induce the proinflammatory cytokine IL-6 in corneal cells via Toll-like receptor 9 (J. Gen. Virol., 2006 87: 2161). Vascular endothelial growth factor (VEGF) and the tissue damaging enzyme matrix metalloproteinase 9 (MMP-9) are known angiogenic factors involved in the pathogenesis of HSK.Here we ask if HSV DNA and HSV neutralized IC induce the production of VEGF and MMP-9 by corneal cells and human macrophage-monocytic cells (THP-1).
THP-1 cells, corneal epithelial cells (HCE) and primary corneal fibroblasts (HCRF) were transfected with HSV-1 (McKrae and MP strain) DNA or treated with HSV-IgG(IC). After 24 hours incubation, supernatants were harvested and tested for the presence of VEGF and MMP-9 by ELISA.
HCRF produced large amount of VEGF (1,000pg/ml) after transfection with HSV-DNA or with the treatment of IC (McKrae IC: 1,650pg/ml and MP IC: 1,500pg/ml), however no VEGF was found in the supernatant of HCRF after active viral or UV inactivated viral infection. In contrast, HCE did not produce VEGF with HSV-DNA or IC, although a small amount of VEGF was detected in the supernatant of HCE with infection of both the McKrae and MP strain of HSV or UV-HSV. THP-1 cells produced a moderate amount of VEGF when infected with live or UV inactivated HSV. The MP strain is a more potent producer in THP-1 cells. In the supernatant of THP-1 cells transfected with MP DNA or treated with McKrae or MP IC, large amount of VEGF was found (MP DNA: 740pg/ml, McKrae or MP IC: 1,000-1,180pg/ml). HCE and HCRF did not produce MMP-9 after infection with live or UV- HSV,transfection with viral DNA or treatment with IC. However, MMP-9 is constitutively produced in the supernatant obtained from THP-1 cells (25ng/ml). When THP-1 cells were transfected with MP-DNA or treated with MP-IC, 2-2.5 times more MMP-9 was found in the supernatant.
VEGF and MMP-9 were produced in response to HSV DNA transfection and IC treatment. Corneal fibroblasts and infiltrating monocyte -macrophages are shown to be the major producers of these angiogenic factors upon exposure to these viral components.
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