Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression

To continue our investigation of the cellular events that occur following h uman CMV (HCMV) infection, we focused on the regulation of cellular activat ion following viral binding to human monocytes, First, we showed that viral binding induced a number of immunoregulatory genes (IL-1 beta, A20, NF-kap pa B-p105/p50, and I kappa B alpha) in unactivated monocytes and that neutr alizing Abs to the major HCMV glycoproteins, gB (UL55) and pH (UL75), inhib ited the induction of these genes. Nest, se demonstrated that these viral l igands directly up-regulated monocyte gene expression upon their binding to their appropriate cellular receptors, We then investigated if HCMV binding also resulted in the translation and secretion of cytokines. Our results s howed that HCMV binding to monocytes resulted in the production and release of IL-1 beta protein. Because these induced gene products have NF-kappa B sites in their promoter regions, we nest examined whether there was an up-r egulation of nuclear NF-kappa B levels. These experiments shelved that, in fact, NF-kappa B was translocated to the nucleus following, viral binding o r purified viral ligand binding, Changes in I kappa B alpha levels correlat ed with the changes in NF-kappa B translocation, Lastly, we demonstrated th at p38 kinase activity played a central role in IL-1 beta production and th at it was rapidly up-regulated following infection. These results support o ur hypothesis that HCMV initiates a signal transduction pathway that lends to monocyte activation and pinpoints a potential mechanism whereby HCMV inf ection of monocytes can result in profound pathogenesis, especially in chro nic inflammatory-type conditions.