Marmoset Viral Hepatic Inflammation Induced by Hepatitis C Virus Core Protein via IL-32

Abstract

Common marmosets infected with GB virus-B (GBV-B) chimeras containing hepatitis C virus (HCV) core and envelope proteins (CE1E2p7) developed more severe hepatitis than those infected with HCV envelope proteins (E1E2p7), suggesting that HCV core protein might be involved in the pathogenesis of viral hepatitis. The potential role of HCV core in hepatic inflammation was investigated. Six individual cDNA libraries of liver tissues from HCV CE1E2p7 or E1E2p7 chimera-infected marmosets (three animals per group) were constructed and sequenced. By differential expression gene analysis, 30 of 632 mRNA transcripts were correlated with the immune system process, which might be associated with hepatitis. A protein-protein interaction network was constituted by STRING database based on these 30 differentially expressed genes (DEGs), showing that IL-32 might play a central regulatory role in HCV core-related hepatitis. To investigate the effect of HCV core protein on IL-32 production, HCV core expressing and mock constructs were transfected into Huh7 cells. IL-32 mRNA and secretion protein were detected at significantly higher levels in cells expressing HCV core protein than in those without HCV core expression (P < 0.01 and P < 0.001, respectively). By KEGG enrichment analysis and using the specific signaling pathway inhibitor LY294002 for inhibition of PI3K, IL-32 expression was significantly reduced (P < 0.001). In conclusion, HCV core protein induces an increase of IL-32 expression via the PI3K pathway in hepatic cells, which played a major role in development of HCV-related severe hepatitis.

Molecular interactions and functions of IL-32

“…92 However, IL-32 has been shown to promote HCV hepatic inflammation in two separate studies. 125,149…”

Hepatic interleukin 32 attenuates liver injury through repression of necroptosis in cholestasis

“…Necroptosis is induced by inhibition of the PI3K/Akt expression 30 . Furthermore, p‐Akt, as the upstream of IL‐32, participates in the regulation of numerous diseases 31 . The expression of p‐Akt is upregulated in the liver of ANIT‐induced cholestatic mice 32 .…”

“…30 Furthermore, p-Akt, as the upstream of IL-32, participates in the regulation of numerous diseases. 31 The expression of p-Akt is upregulated in the liver of ANIT-induced cholestatic mice. 32 In line with these findings, we observed that both IL-32 and p-Akt expressions were elevated in PLC/PRF/5-ASBT cells under the treatment of bile acids and were positively correlated with the bile acid concentration, while inhibition of p-Akt decreased the expression of IL-32 under bile acid stimulation.…”

Hepatitis C virus core protein

“…Microarray analysis on immortalized human hepatocytes suggested that the HCV core protein induces inflammatory cytokines through the STAT3 signaling pathway [ 41 ] and extracellular HCV core protein activations of STAT3 in human monocytes, macrophages, and dendritic cells (DCs) were observed to related to an interleukin (IL)-6 pathway [ 22 ]. HCV core protein in a primate model was found to induce hepatic inflammation through stimulated expression of IL-32 via phosphoinositide 3-kinases pathway [ 42 ]. On the other hand, the anti-inflammatory effects by the HCV core protein were also evidenced.…”