Abstract
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
Highlights
The liver is one of the largest organs in the body, with diverse metabolic and immunologic functions
Stimulation with the respective ligands led to suppression of TLR4 and TLR6 in liver sinusoidal endothelial cells (LSEC) or TLR4, TLR5 and TLR6 in hepatic star cells (HSC)
Antiviral potential of non-parenchymal liver cells (NPC) was restricted to TLR3 activation that led to secretion of type I and type III interferons. (II) interferon alpha/beta receptor 2 (IFNAR2) was shown to mediate the antiviral effect, IFNA and IFNB1 did not seemed to be involved. (III) LSECs, but not Kupffer cells (KC) and HSCs, isolated from HCV-infected patients showed hyperresponsiveness to poly(I:C) treatment, as known for primary human hepatocytes (PHH) [15]
Summary
The liver is one of the largest organs in the body, with diverse metabolic and immunologic functions. The NPC fraction contains about 15% Kupffer cells (KC), 19% liver sinusoidal endothelial cells (LSEC), 5% hepatic star cells (HSC) and 1% lymphocytes and leukocytes, calculated for the entire cell population [1,2,3,4]. KCs represent the liver-resident macrophage population localized in the portal areas. These cells have a high phagocytic activity to remove pathogens like viruses, bacteria and endotoxins from the blood stream [5,6]. LSECs form a fenestrated lining within the hepatic sinusoids that represents a barrier between the sinusoidal lumen and the space of Disse [7,8], where HSCs are located [9]. As part of the innate immune system, NPC are equipped with a set of pattern recognition receptors, such as Toll-like receptors (TLR), which mediate innate immune responses after recognition of pathogen-associated molecular patterns, as shown for murine [12,13] and human cells [14]
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