Decreased Cytomegalovirus Expression Following Proinflammatory Cytokine Treatment of Primary Human Astrocytes

Abstract

Understanding the influence of immune effector mechanisms on CMV infection of the CNS may facilitate the development of immunotherapies for viral encephalitis. Using cultures of highly purified, fully permissive primary human astrocytes, proinflammatory cytokines, but not antiinflammatory cytokines or β-chemokines, were found to inhibit CMV expression, DNA synthesis, and replication. Treatment with certain proinflammatory cytokines 24 h before CMV infection markedly suppressed viral expression in astrocytes. TNF-α, IL-1β, and IFN-γ all inhibited CMV expression (70 ± 4.2%, 65 ± 3.4%, and 82 ± 3.6% inhibition of viral expression, respectively, n = 5). In contrast, no viral suppression was observed following IL-6 treatment. Suppressive activity was dependent on the addition of cytokines before CMV infection. Cytokine pretreatment did not affect CMV entry into primary astrocytes, and the observed cytokine-induced suppressive activity was not affected by the NO synthase inhibitor NG-monomethyl-l-arginine (NGMA). Instead, the suppressive effect appeared to be mediated through a mechanism involving inhibition of CMV major immediate early promoter activity. These results support the hypothesis that proinflammatory cytokines possess anti-CMV activity in brain cells and may lead to new interventions for CMV encephalitis based upon immunotherapy.

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…78,79 Microglial cell-derived TNF-a and T cell-derived IFN-c inhibit CMV replication in astrocytes by suppressing transcription from the CMV MIEP. 37 This acute cytokine response is regulated by the anti-inflammatory cytokine IL-10. 80 Although lack of IL-10 has little effect on viral load, it leads to a severely dysregulated IFN-c response and renders CMV brain infection lethal.…”

“…35,36 Treatment of human astrocytes with selected proinflammatory cytokines (IL-1b, tumor necrosis factor (TNF)-a and interferon (IFN)-c) induces an antiviral state by blocking viral replication at the level of transcription from the major immediate early promoter (MIEP). 37,38 Endothelial cells of the brain microvasculature also support lytic infection, [39][40][41] and CMV infection of endothelial cells may be a potential means the virus uses to enter the CNS. Interestingly, HCMV infection of endothelial cells also promotes monocyte recruitment, transendothelial migration and infection, which may be another mechanism of viral dissemination into the brain.…”

Human Cytomegalovirus Infection Inhibits Tumor Necrosis Factor Alpha (TNF-α) Signaling by Targeting the 55-Kilodalton TNF-α Receptor

“…However, TNF-␣ has been shown to activate or inhibit viral IE gene expression, depending on the differentiation state of monocytic cells, such that in differentiated, permissive cells, the HCMV major IE promoter is strongly inhibited by TNF-␣ (16,40). Also, TNF-␣ has been shown to inhibit virus production in certain HCMV-infected cell types (4,10). Clearly, TNF-␣ has profound effects on cells.…”

An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

“…25,26 TNFa has also been shown to negatively regulate the CMV immediate-early promoter depending on the cell type studied. 27,28 Based on our in vitro studies and that of others, the human CMV immediate-early promoter may behave like the IL-1/IL-6 enhancer-promoter construct. The difference found between the IL-1/IL-6 hybrid and CMV promoter in response to LPS in RAW cells suggests that we cannot exclude that both promoters may respond differently in other target cells.…”