S-Adenosyl-Methionine and Betaine Improve Early Virological Response in Chronic Hepatitis C Patients with Previous Nonresponse

Treatment of chronic hepatitis C (CHC) with pegylated interferon (pegIFN ) and ribavirin results in a sustained response in approximately half of patients. Viral interference with IFN signal transduction through the Jak-STAT pathway might be an important factor underlying treatment failure. S-adenosyl-L-methionine (SAMe) and betaine potentiate IFN signaling in cultured cells that express hepatitis C virus (HCV) proteins, and enhance the inhibitory effect of IFN on HCV replicons. We have performed a clinical study with the aim to evaluate efficacy and safety of the addition of SAMe and betaine to treatment of CHC with pegIFN /ribavirin

Association between Serum Interleukin-6 Concentrations and Mortality in Older Adults: The Rancho Bernardo Study

Background: Interleukin-6 (IL-6) may have a protective role in acute liver disease but a detrimental effect in chronic liver disease. It is unknown whether IL-6 is associated with risk of liver-related mortality in humans. Aims: To determine if IL-6 is associated with an increased risk of all-cause, cardiovascular disease (CVD), cancer, and liverrelated mortality. Methods: A prospective cohort study included 1843 participants who attended a research visit in 1984–87. Multiple covariates were ascertained including serum IL-6. Multivariable-adjusted Cox proportional hazards regression analyses were used to examine the association between serum IL-6 as a continuous (log transformed) variable with all-cause, CVD, cancer, and liver-related mortality. Patients with prevalent CVD, cancer and liver disease were excluded for cause-specific mortality. Results: The mean (6 standard deviation) age and body-mass-index (BMI) of participants was 68 (610.6) years and 25 (63.7) Kg/m 2, respectively. During the 25,802 person-years of follow-up, the cumulative all-cause, CVD, cancer, and liverrelated mortality were 53.1 % (N = 978), 25.5%, 11.3%, and 1.3%, respectively. The median (6IQR) length of follow-up was 15.3610.6 years. In multivariable analyses, adjusted for age, sex, alcohol, BMI, diabetes, hypertension, total cholesterol, HDL, and smoking, one-SD increment in log-transformed serum IL-6 was associated with increased risk of all-cause, CVD, cancer, and liver-related mortality, with hazard ratios of 1.48 (95 % CI, 1.33–1.64), 1.38 (95 % CI, 1.16–1.65), 1.35 (95 % CI, 1.02–1.79)

Interleukin-6 Induces Gr-1+CD11b+ Myeloid Cells to Suppress CD8+ T Cell-Mediated Liver Injury in Mice

Agonist antibodies against CD137 (4-1BB) on T lymphocytes are used to increase host anti-tumor immunity, but often leading to severe liver injury in treated mice or in patients during clinical trials. Interleukin-6 (IL-6) has been reported to protect hepatocyte death, but the role of IL-6 in protecting chronic T cell-induced liver diseases is not clearly defined due to lack of relevant animal models. We aimed to define the role of IL-6 in CD8+ T cell-mediated liver injury induced by a CD137 agonistic mAb (clone 2A) in mice.We expressed IL-6 in the liver by hydrodynamic gene delivery in mice treated with 2A or control mAb and studied how IL-6 treatment affected host immunity and T cell-mediated liver injury. We found that ectopic IL-6 expression in the liver elevated intrahepatic leukocyte infiltration but prevented CD8+ T cell-mediated liver injury. In IL-6 treated mice, CD8+ T cells proliferation and IFN-γ expression were inhibited in the liver. We discovered that IL-6 increased accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in the liver and spleen. These MDSCs had the ability to inhibit T cells proliferation and activation. Finally, we showed that the MDSCs were sufficient and essential for IL-6-mediated protection of anti-CD137 mAb-induced liver injury.We concluded that IL-6 induced Gr-1+CD11b+ MDSCs in the liver to inhibit T cell-mediated liver injury. The findings have defined a novel mechanism of IL-6 in protecting liver from CD8+ T cell-mediated injury

Elimination of Hepatitis C Virus from Hepatocytes by a Selective Activation of Therapeutic Molecules

To eliminate hepatitis C virus (HCV) from infected hepatocytes, we generated two therapeutic molecules specifically activated in cells infected with HCV. A dominant active mutant of interferon (IFN) regulatory factor 7 (IRF7) and a negative regulator of HCV replication, VAP-C (Vesicle-associated membrane protein-associated protein subtype C), were fused with the C-terminal region of IPS-1 (IFNβ promoter stimulator-1), which includes an HCV protease cleavage site that was modified to be localized on the ER membrane, and designated cIRF7 and cVAP-C, respectively. In cells expressing the HCV protease, cIRF7 was cleaved and the processed fragment was migrated into the nucleus, where it activated various IFN promoters, including promoters of IFNα6, IFNβ, and IFN stimulated response element. Activation of the IFN promoters and suppression of viral RNA replication were observed in the HCV replicon cells and in cells infected with the JFH1 strain of HCV (HCVcc) by expression of cIRF7. Suppression of viral RNA replication was observed even in the IFN-resistant replicon cells by the expression of cIRF7. Expression of the cVAP-C also resulted in suppression of HCV replication in both the replicon and HCVcc infected cells. These results suggest that delivery of the therapeutic molecules into the liver of hepatitis C patients, followed by selective activation of the molecules in HCV-infected hepatocytes, is a feasible method for eliminating HCV

Inducible inactivation of Notch1 causes nodular regenerative hyperplasia in mice

The discovery that the human Jagged1 gene (JAG1) is the Alagille syndrome disease gene indicated that Notch signaling has an important role in bile duct homeostasis. The functional study of this signaling pathway has been difficult because mice with targeted mutations in Jagged1, Notch1, or Notch2 have an embryonic lethal phenotype. We have previously generated mice with inducible Notch1 disruption using an interferon-inducible Cre-recombinase transgene in combination with the loxP flanked Notch1 gene. We used this conditional Notch1 knockout mouse model to investigate the role of Notch1 signaling in liver cell proliferation and differentiation. Deletion of Notch1 did not result in bile duct paucity, but, surprisingly, resulted in a continuous proliferation of hepatocytes. In conclusion, within weeks after Notch1 inactivation, the mice developed nodular regenerative hyperplasia without vascular changes in the liver

Synapses form in skeletal muscles lacking neuregulin receptors.

The formation of the neuromuscular junction (NMJ) is directed by reciprocal interactions between motor neurons and muscle fibers. Neuregulin (NRG) and Agrin from motor nerve terminals are both implicated. Here, we demonstrate that NMJs can form in the absence of the NRG receptors ErbB2 and ErbB4 in mouse muscle. Postsynaptic differentiation is, however, induced by Agrin. We therefore conclude that NRG signaling to muscle is not required for NMJ formation. The effects of NRG signaling to muscle may be mediated indirectly through Schwann cells

Expression of Hepatitis C Virus Proteins Inhibits Interferon alpha Signaling in the liver of transgenic mice

Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. The majority of patients treated with interferon alpha do not have a sustained response with clearance of the virus. The molecular mechanisms underlying interferon resistance are poorly understood. Interferon-induced activation of the Jak-STAT (signal transducer and activator of transcription) signal transduction pathway is essential for the induction of an antiviral state. Interference of viral proteins with the Jak-STAT pathway could be responsible for interferon resistance in patients with chronic HCV. Methods: We have analyzed interferon-induced signal transduction through the Jak-STAT pathway in transgenic mice that express HCV proteins in their liver cells. STAT activation was investigated with Western blots, immunofluorescence, and electrophoretic mobility shift assays. Virus challenge experiments with lymphocytic choriomeningitis virus were used to demonstrate the functional importance of Jak-STAT inhibition. Results: STAT signaling was found to be strongly inhibited in liver cells of HCV transgenic mice. The inhibition occurred in the nucleus and blocked binding of STAT transcription factors to the promoters of interferon-stimulated genes. Tyrosine phosphorylation of STAT proteins by Janus kinases at the interferon receptor was not inhibited. This lack in interferon response resulted in an enhanced susceptibility of the transgenic mice to infection with a hepatotropic strain of lymphocytic choriomeningitis virus. Conclusions: Interferon-induced intracellular signaling is impaired in HCV transgenic mice. Interference of HCV proteins with interferon-induced intracellular signaling could be an important mechanism of viral persistence and treatment resistance