Interference with KCTD9 inhibits NK cell activation and ameliorates fulminant liver failure in mice.

BACKGROUND: Potassium channel tetramerisation domain containing 9 (KCTD9), a member of KCTD family with a DNA-like pentapeptide repeat domain, was found to be increased particularly in NK cells of patients with HBV-induced acute-on-chronic liver failure (HBV-ACLF) and experimental viral fulminant hepatitis. Knockdown of KCTD9 in immortalized NK cells inhibits cytokines production and cytotoxicity. As NK cell activation was shown to exacerbate liver damage in viral fulminant hepatitis, we propose that target inhibition of KCTD9 may prohibit NK cells activity and thus ameliorate liver damage in viral fulminant hepatitis. RESULT: Hydrodynamic delivery of plasmid expressing short-hairpin RNA against KCTD9 resulted in impaired NK cells function as demonstrated by reduced cytokine production and cytotoxicity, and ameliorated liver injury as manifested by improved liver histology and survival rate. In contrast, delivery of plasmid expressing KCTD9 led to deteriorated disease progression. CONCLUSION: Interference with KCTD9 expression exert beneficial effect in viral fulminant hepatitis therapy. Such effect may be mediated by impairment of NK cell activation.

Functional restoration of CD56bright NK cells facilitates immune control via IL-15 and NKG2D in patients under antiviral treatment for chronic hepatitis B.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) is intrinsically immunogenic, with long-lasting immune control in many patients. However, the mechanisms and key cell types underlying effective immune control are incompletely understood. METHODS: We studied the restoration of natural killer (NK) cell numbers and function post antiviral treatment in 52 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who received telbivudine (LdT) for 48 weeks. Blood samples were collected at week 0, 12, 24, 36, and 48 and tested for HBV DNA, hepatitis B surface antigen (HBsAg), HBeAg, liver enzymes, and NK cell parameters. RESULTS: Compared with baseline, the number of peripheral CD3-CD56bright NK cells increased significantly from week 24 to 48, especially in patients with baseline alanine transaminase (ALT) two- to fivefold the upper line of normal (ULN) or HBV DNA <9 log10 copies/ml. Expression (number and density) of activating receptors NKG2D and NKp46 on CD3-CD56bright NK cells was enhanced, while inhibitory receptor NKG2A decreased. Notably, numbers of CD3-CD56bright or NKG2D+CD3-CD56bright NK cells were significantly better restored in patients with HBeAg seroconversion. NK cell activating serum interleukin 15 (IL-15) was significantly increased during LdT treatment, especially in HBeAg seroconverters. LdT significantly enhanced expression of NKG2D and IL-15 in cultures of purified peripheral NK cells from treatment-naïve HBeAg-positive CHB patients. CONCLUSIONS: Functional restoration of CD56bright NK cells via upregulation of IL-15 and NKG2D is a novel activity of LdT and likely other antivirals, independent of its effect on HBV replication. This also demonstrates the importance of host immune restoration in controlling chronic HBV infection.

Effect of caesarean section on maternal and foetal outcomes in acute fatty liver of pregnancy: a systematic review and meta-analysis.

Several studies have reported a positive association between caesarean section for expeditious pregnancy termination and perinatal outcomes in acute fatty liver of pregnancy (AFLP); however, the risks remain unclear and independent studies have reported conflicting findings. In this meta-analysis, we aimed to confirm the relationship between caesarean section and perinatal outcomes in AFLP. The PubMed, Embase, and China National Knowledge Infrastructure databases were searched (until July 17, 2015) for observational clinical studies focusing on the association between caesarean section and perinatal outcomes in AFLP. Data were extracted and processed independently by 2 authors. We also compared caesarean section with vaginal delivery to further investigate this relationship. We observed that 2 of the 3 primary outcomes in caesarean section exhibited positive effects-the maternal mortality rate was 44% lower (relative risk [RR], 0.56 [0.41-0.76]) and perinatal mortality rate was also reduced (RR, 0.52 [0.38-0.71]), compared to those for vaginal delivery. We did not find any associations between caesarean section and perinatal outcomes in AFLP in terms of neonatal mortality type and maternal multiple organ complications. These findings emphasise the significant prognostic value and clinical implications of caesarean section in AFLP, and suggest that the adverse outcomes should be reduced.

SOCS3 expression correlates with severity of inflammation in mouse hepatitis virus strain 3-induced acute liver failure and HBV-ACLF.

Recently, suppressor of cytokine signaling-3 (SOCS3) has been shown to be an inducible endogenous negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway which is relevant in inflammatory response, while its functions in acute liver failure and HBV-induced acute-on-chronic liver failure (HBV-ACLF) have not been fully elucidated. In this study, we explored the role of SOCS3 in the development of mouse hepatitis virus strain 3 (MHV-3)-induced acute liver failure and its expression in liver and peripheral blood mononuclear cells (PBMCs) of patients with HBV-ACLF. Inflammation-related gene expression was detected by real-time PCR, immunohistochemistry and Western blotting. The correlation between SOCS3 level and liver injury was studied. Our results showed that the SOCS3 expression was significantly elevated in both the liver tissue and PBMCs from patients with HBV-ACLF compared to mild chronic hepatitis B (CHB). Moreover, a time course study showed that SOCS3 level was increased remarkably in the liver of BALB/cJ mice at 72 h post-infection. Pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, were also increased significantly at 72 h post-infection. There was a close correlation between hepatic SOCS3 level and IL-6, and the severity of liver injury defined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respectively. These data suggested that SOCS3 may play a pivotal role in the pathogenesis of MHV-3-induced acute liver failure and HBV-ACLF.

CD69+NK cells contribute to the murine hepatitis virus strain 3-induced murine hepatitis.

The role of hepatic CD69+ natural killer (NK) cells in virus-induced severe liver injury and subsequent hepatic failure is not well defined. In this study, a mouse model of fulminant liver failure (FHF) induced by murine hepatitis virus strain 3 (MHV-3) was used to study the role of hepatic CD69+NK cells in the development of FHF. The CD69 expression in NK cells in the liver, spleen, bone marrow and peripheral blood was detected by using flow cytometry. The correlation between the CD69 level in hepatic NK cells and liver injury was studied. The functional marker (CD107a), and activating and inhibitory receptor (NKG2D and NKG2A) expressed on CD69+NK cells and CD69-NK cells were detected by using flow cytometry. Pro-inflammatory cytokines (IL-9, IFN-γ and TNF-α) were also examined by using intracellular staining. After MHV-3 infection, the number of CD69+NK cells in the liver of BALB/cJ mice was increased markedly and peaked at 72 h post-infection. Similar changes were also observed in the spleen, bone marrow and peripheral blood. Meanwhile, the CD69 expression in hepatic NK cells was highly correlated with the serum level of ALT and AST. The expression of CD107a and NKG2D, as well as the production of TNF-α, IFN-γ and IL-9 in hepatic CD69+NK cells was all significantly up-regulated during 48-72 h post-infection. In contrast, the NKG2A expression was increased in hepatic CD69-NK cells but not in CD69+NK cells. These results suggested that hepatic CD69+NK cells play a pivotal role in the pathogenesis of FHF by enhancing degranulation and cytotoxic ability of NK cells and increasing the production of pro-inflammatory cytokines.