Interleukin-6 Rescues Lymphocyte from Apoptosis and Exhaustion Induced by Chronic Hepatitis C Virus Infection.

Chronic hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion and apoptosis to potentially assist viral persistence inside the host, eventually leading to exacerbated conditions of inflammation and hepatocarcinogenesis. Growing evidence suggests that spontaneous apoptosis of peripheral blood mononuclear cells (PBMCs) could be one of the potential immune impairment mechanisms in chronic viral infection. Interleukin-6 (IL-6) is a pleiotropic cytokine that plays an essential role in regulating immune and inflammatory responses. Owing to its known role in priming T cell growth, differentiation, and inhibition of lymphocyte apoptosis, we investigated the protective effect of IL-6 in rescuing lymphocytes from apoptosis and functional exhaustion in chronic HCV infection. The expression pattern of antiapoptotic (Mcl-1 and Bcl-2), proapoptotic (caspase-3 and Bim) genes along with interferon gamma (IFN-γ) and T cell inhibitory receptor (TIM-3) was analyzed before and after in vitro IL-6 treatment of patient-derived PBMCs. It was observed that the expression of antiapoptotic genes, Mcl-1 and Bcl-2 increased (threefolds and twofolds, respectively) and there was a considerable downregulation in T cell inhibitory receptor (TIM-3) and caspase-3. Similarly, the capacity of PBMCs to produce IFN-γ was also significantly increased (p < 0.001) depicting the promising nature of IL-6 in enhancing lymphocyte effector function. Summing it up, the study supports the positive role of IL-6 in rescuing PBMC population; however, the cytokine alone is not sufficient to sustain the adaptive immunity. It could be used as a potential candidate for combinational therapy along with other regulatory factors for ex vivo enhancement of lymphocyte and may help in moving one step toward adoptive T cell therapy in chronic HCV infection.

Interleukin-6: A promising cytokine to support liver regeneration and adaptive immunity in liver pathologies.

Liver pathologies (fibrosis, cirrhosis, alcoholic, non-alcoholic diseases and hepatocellular carcinoma) represent one of the most common causes of death worldwide. A number of genetic and environmental factors contribute to the development of liver diseases. Interleukin-6 (IL-6) is a pleiotropic cytokine, exerting variety of effects on inflammation, liver regeneration, and defence against infections by regulating adaptive immunity. Due to its high abundance in inflammatory settings, IL-6 is often viewed as a detrimental cytokine. However, accumulating evidence supports the view that IL-6 has a beneficial impact in numerous liver pathologies, due to its roles in liver regeneration and in promoting an anti-inflammatory response in certain conditions. IL-6 promotes proliferation, angiogenesis and metabolism, and downregulates apoptosis and oxidative stress; together these functions are critical for mediating hepatoprotection. IL-6 is also an important regulator of adaptive immunity where it induces T cell differentiation and regulates autoimmunity. It can augment antiviral adaptive immune responses and mitigate exhaustion of T cells during chronic infection. This review focuses on studies that present IL-6 as a key factor in regulating liver regeneration and in supporting effector immune functions and suggests that these functions of IL-6 can be exploited in treatment strategies for liver pathologies.

Ionotropic Purinergic Receptors P2X4 and P2X7: Proviral or Antiviral? An Insight into P2X Receptor Signaling and Hepatitis C Virus Infection.

Purinergic P2X receptors are plasma membrane bound, ATP-gated ion channels that are expressed on wide range of cells and respond to varying ATP concentrations in extracellular environment. Upon activation they increase membrane permeability for Ca(2+) ions and trigger a cascade of signaling complexes. During the course of hepatitis C virus (HCV) infection, ATP is released from the infected hepatocyte, which binds with Purinergic receptors (P2X) on peripheral blood mononuclear cells (PBMCs) and initiate downstream signaling pathways by disturbing the ionic balance of the cell. The present study investigates quantitative expression of P2X7 and P2X4 along with selected host genes PEPCK, transforming growth factor ß (TGF-ß), MAPK, Rho, and Akt in PBMCs of chronic HCV infection patients. PBMCs were isolated from collected blood samples of study subjects. Transcript analysis of P2X7, P2X4, and targeted downstream genes was done using quantitative real-time polymerase chain reaction. Relative expression analysis was performed by unpaired Student's t test on GraphPad Prism version 5. We found a notable increase of threefolds and 1.8-folds in the expression of P2X7 and P2X4 receptors in treatment naïve category while the expression of PEPCK, TGF-ß, MAPK, AKT, and Rho A increased by 2.8, 1.9, 2.2, 2.2, and 1.8-folds, respectively. In sustained virological response patients, P2X7 significantly increased up to 3.5-folds while the expression of P2X4 receptor was increased up to twofold. In third category, treatment nonresponder, the expression of P2X7, P2X4 receptors, and targeted markers remained un-altered. This study deals with two major aspects of P2X4 and P2X7 receptors in PBMCs of chronic HCV individuals. One is their role in providing antiviral immunity to host against HCV; second aspect is the role of P2X receptors in inducing HCV pathogenesis via AKT, TGF-ß, Rho A, PEPCK, and MAPK expression.

IL-22: a promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a growing concern all over the world. With the number of patients rising exponentially with each passing day, HCC is a problem that needs immediate attention. Currently, available treatment strategies focus on controlling the damage after the development of HCC. The options available from chemo- and radio-embolization to surgical resection and transplantation are not efficacious as required due to the complex nature of the disease. Liver regeneration and tissue healing are the subject of great interest today. Interleukin-22 (IL-22) is a cytokine with the ability to regenerate and therefore reverse the injuries caused by a wide range of agents. IL-22 acts via STAT molecule and controls the activity of a wide variety of cell survival and proliferation genes. Experimental data has given a positive insight into the role of IL-22 in inhibition of viral and alcohol-induced hepatocellular carcinoma. A further insight into the nature of IL-22 and the factors that can be manipulated in controlling the activity of IL-22 can help to counter the menace caused by the devastating effects of HCC.

Interleukin- 28B: a prognostic marker in interferon based therapy of chronic HCV patients of the Pakistan with variable treatment response.

Unfortunately Pakistan carries one of the world's highest burdens of chronic hepatitis along with mortality due to liver failure and hepatocellular carcinoma. Scientists after extensive research have come up with this outcome that host genetics play a vital role in dictating the type of treatment response produced by the patients. In 2009, a genome wide association study (GWAS) revealed that genetic variants in close proximity to the IL28B (IFNL3) gene predicted greater likelihood of achieving sustained virological response (SVR) following treatment with pegylated IFN-alpha (peg INF-α) and ribavirin. IL28B (rs12979860 and rs8099917) single nucleotide polymorphisms (SNPs) have been recently found among the Pakistani population associated with response to chronic HCV infection INF-α + ribavirin therapy. Therefore, this study was aimed to investigate the IL-28B protein levels in the HCV infected patients. The findings showed that the serum IL28B protein level was higher in HCV infected patients as compared to healthy controls (7.743 ± 1.519 pg/mL versus 1.600 ± 0.06054 [mean ± SEM], p < 0.05). When the chronic hepatitis C (CHC) patients were further categorized into SVR and NR (non-responders) on the basis of treatment outcomes, the mean IL28B protein level was higher in NRs (15.54 ± 3.609) than SVRs (4.259 ± 0.3405). Thus, there was a significant correlation between IL28B protein level in varied treatment response (p < 0.05). However, the findings can lead us to propose that IL28B could be used as a prognostic marker. It can help the clinicians to take better pre-informed decisions whether to take combinational therapy of peg IFN ± ribavirin or not. This will in turn prove beneficial for the patient by saving patients' health, treatment cost and undesirable treatment side effects.