Abstract
Hypericum perforatum ( H . perforatum ) ethanol extract has been found to inhibit lipopolysaccharide-induced production of inflammatory mediators and cytokines in cultured macrophages. Therefore, it may be able to protect the host from excessive inflammation during viral infection. In the current study, the immune-regulatory effect of H . perforatum extract was evaluated in A549 lung epithelial cells and BALB/c mice exposed to Influenza A/PR/8/34 H1N1 virus. In A549 cells, the extract (30 µg/mL) significantly inhibited influenza virus induced monocyte chemotactic protein (MCP)-1 and interferon-γ induced protein 10 kD (IP-10), but dramatically increased interleukin-6 (IL-6). In mice inoculated intranasally with 107.9 EID50 of Influenza A/PR/8/34 H1N1 (high dose), daily oral treatment of H . perforatum extract at a rate of 110 mg/kg of body weight increased lung viral titer, bronchoalveolar lavage (BAL) pro-inflammatory cytokine and chemokine levels, and the infiltration of pro-inflammatory cells in the lung 5 days post-inoculation, as compared to ethanol vehicle treated mice. Transcription of suppressor of cytokine signaling 3 (SOCS3) was increased by H . perforatum extract both in A549 cells and BALB/c mice, which could have interrupted anti-viral immune response and thus led to the inefficient viral clearance and increased lung inflammation. H . perforatum treatment resulted in minor reduction in viral titer without affecting body weight when mice were inoculated with a lower dose (~105.0 EID50) and H . perforatum was applied in the later phase of infection. Mice challenged intranasally with high dose of influenza virus (107.9 EID50) suffered from a higher mortality rate when dosed with H . perforatum extract. In conclusion, the current study showed that SOCS3 elevation by H . perforatum may cause impaired immune defense against influenza virus infection and lead to higher mortality.
Highlights
Influenza virus has been a major public health burden for centuries, affecting 10-20% of the general population and causing approximately 36,000 deaths annually in the United States [1,2]
The background levels of induced protein 10 kD (IP-10) and monocyte chemotactic protein (MCP)-1 produced by A549 cells were decreased when treated with H. perforatum extract
In contrast to our prior observation in lipopolysaccharide (LPS)-induced macrophages, we found that the H. perforatum extract drastically increased IL-6 production by A549 cells, with or without virus stimulation (Figure 1)
Summary
Influenza virus has been a major public health burden for centuries, affecting 10-20% of the general population and causing approximately 36,000 deaths annually in the United States [1,2]. The host immune system is activated to contain and resolve the infection. Certain strains of influenza virus, such as H5N1, are more likely to induce excessive cytokine release and immune cell exudation [4]. This so-called ‘cytokine storm’ scenario, features elevated levels of cytokines and chemokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, and interferon (IFN)-γ, as well as the exudation of monocytes, macrophages, and neutrophils. ‘Cytokine storm’ causes tissue damage, impairs normal mucosal membrane and may induce airway blockage, making it a risk factor for the higher mortality associated with these virulent strains [7,8]. Alleviating inflammation during influenza virus infection could potentially be beneficial
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