Induction of IL-6 in Transcriptional Networks in Corneal Epithelial Cells after Herpes Simplex Virus Type 1 Infection

PURPOSE. To determine the transcriptional responses of human corneal epithelial cells (HCECs) after herpes simplex virus type (HSV)-1 infection and to identify the critical inflammatory element( s). METHOD. Immortalized HCECs were infected with HSV-1, and the global transcriptional profile determined. Molecular signaling networks were constructed from the HSV-1-induced transcriptomes. The relationships of the identified networks were confirmed by real-time-PCR and ELISA. Contributions of the critical network nodes were further evaluated by protein array analyses as candidates for inflammatory element induction. RESULTS. HSV-1 infection induced a global transcriptional response, with 412 genes significantly activated or suppressed compared with mock-infected HCECs (P < 0.05, 2< or 0.5> threshold). Infection by UV-inactivated HSV-1 did not induce significant transcriptional activity. Network analysis showed that the HSV-1-induced transcriptomes were associated with JUN N-terminal kinase, p38, extracellular signal-regulated kinase, and nuclear factor kappa-B signaling pathways. These findings indicate that interleukin (IL)-6 and vascular endothelial growth factor (VEGF) probably serve as critical nodes of signaling events. ELISA and protein array analyses verified the induction of the inflammatory elements by HSV infection. Blocking the induction of IL-6 significantly reduced the expression of 21 cytokines, including CCL7, CCL8, CXCL6, transforming growth factor-beta 2, platelet-derived growth factor, interferon-gamma, IL-2, and VEGF, thus confirming the critical role of IL-6. CONCLUSIONS. HCECs respond to HSV-1 infection by initiating mitogen-activated protein kinase-related transcriptional events, and IL-6 may serve to induce expression of an array of inflammatory mediators. (Invest Ophthalmol Vis Sci. 2010;51:2441-2449) DOI: 10.1167/iovs.09-4624