Summary auto-generated
This study investigated nitric oxide (NO) production in mouse peritoneal macrophages infected with herpes simplex virus type 2 (HSV-2). The researchers found that HSV-2 alone induced minimal NO production in resting macrophages. However, when combined with interferon-gamma (IFN-γ), HSV-2 exerted a significant synergistic effect on NO release. This synergistic effect required infectious virus particles, as inactivated virus showed minimal activity. The researchers also confirmed that iNOS gene expression correlated with NO production. Mechanistic studies using neutralizing antibodies revealed that the synergistic effect depended on autocrine secretion of tumor necrosis factor-alpha (TNF-α), which acted as a second signal to enhance IFN-γ-induced NO production. Importantly, anti-IFN-α/β antibodies had no effect on nitrite production, indicating that TNF-α, rather than type I interferons, was critical for the synergistic response. These findings suggest that HSV-2 infection primes macrophages to produce enhanced amounts of NO when exposed to IFN-γ, potentially contributing to antiviral defense mechanisms.
Key findings
- HSV-2 alone induces minimal nitric oxide production in resting mouse macrophages, but significantly enhances IFN-γ-induced NO production through a synergistic mechanism
- The synergistic effect requires infectious HSV-2 particles and correlates with induction of iNOS gene expression at the mRNA level
- TNF-α mediates the synergistic effect through autocrine signaling, as neutralizing anti-TNF-α antibodies abolished the enhanced NO response while anti-IFN-α/β had no effect
- The synergistic NO induction becomes evident 12-18 hours after HSV-2 infection and IFN-γ stimulation, developing from an additive effect to true synergy by 18 hours
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Abstract
We have analysed the ability of herpes simplex virus type 2 (HSV-2) to induce nitric oxide (NO) production in resting BALB/c mouse peritoneal macrophages. In most experiments, macrophages produced very small amounts of NO upon infection with HSV-2. Mock virus preparations did not induce NO production, and virus inactivation experiments showed that infectious virus was required. Since interferon-gamma (IFN-gamma) is the prototype cytokine that is able to induce significant NO production in macrophages, we found it of interest to examine the influence of HSV-2 infection on the IFN-gamma-induced NO production. The virus exerted a synergistic effect on the IFN-gamma-induced NO release, which was accompanied by induction of the iNOS-gene as revealed by RT-PCR. This effect was largely dependent on the presence of infectious virus particles, since only a minor effect was seen with mock virus and inactivated virus preparations. From experiments with neutralizing antibodies to tumour necrosis factor-alpha (TNF-alpha) and IFN-alpha/beta it was concluded that the synergistic effect is dependent on autocrine secretion of TNF-alpha, which acts as a second signal and synergizes with IFN-gamma in NO production.