Modulation of double-stranded RNA-mediated gene induction by interferon in human umbilical vein endothelial cells

Endothelial cells respond to double-stranded RNA (dsRNA) with expression of a number of important immunomodulatory and inflammatory response genes, including adhesion molecules, cytokines, and antiviral genes. Considerable differences are seen when genes are induced by dsRNA compared with cytokines. Much higher levels of mRNA for interleukin-6 (IL-6), 2',5'-oligoadenylate synthetase (2',5'-OAS), protein kinase (PKR), and interferon (IFN) regulatory factor-1 (IRF-1) result from incubation with dsRNA than with IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), or IFN-alpha, whereas the differences in vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA expression in response to dsRNA, IL-1 beta, and TNF-alpha are relatively minor. IFN-alpha priming enhances responsiveness of some, but not all, genes to dsRNA but not to IL-1 beta, but the optimal time for pretreatment varies considerably among different dsRNA-responsive genes. Protein translation is reduced in human umbilical vein endothelial cells (HUVEC) in response to incubation with dsRNA, and this decrease is accentuated if cells are primed with IFN-alpha. Despite this decrease, IFN-alpha priming causes very high levels of IL-6 protein expression in response to dsRNA but not in response to IL-1 beta or TNF-alpha. These studies demonstrate that priming with class I IFN can enhance the response to dsRNA through the heightened expression of genes that contribute to both the cellular response to viral infection and the host immunologic response.