Chronic Liver Inflammation Research Articles

β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice.

β-Caryophyllene (BCP) is a plant-derived FDA approved food additive with anti-inflammatory properties. Some of its beneficial effects in vivo are reported to involve activation of cannabinoid CB2 receptors that are predominantly expressed in immune cells. Here, we evaluated the translational potential of BCP using a well-established model of chronic and binge alcohol-induced liver injury. In this study, we investigated the effects of BCP on liver injury induced by chronic plus binge alcohol feeding in mice in vivo by using biochemical assays, real-time PCR and histology analyses. Serum and hepatic BCP levels were also determined by GC/MS. Chronic treatment with BCP alleviated the chronic and binge alcohol-induced liver injury and inflammation by attenuating the pro-inflammatory phenotypic `M1` switch of Kupffer cells and by decreasing the expression of vascular adhesion molecules intercellular adhesion molecule 1, E-Selectin and P-Selectin, as well as the neutrophil infiltration. It also beneficially influenced hepatic metabolic dysregulation (steatosis, protein hyperacetylation and PPAR-α signalling). These protective effects of BCP against alcohol-induced liver injury were attenuated in CB2 receptor knockout mice, indicating that the beneficial effects of this natural product in liver injury involve activation of these receptors. Following acute or chronic administration, BCP was detectable both in the serum and liver tissue homogenates but not in the brain. Given the safety of BCP in humans, this food additive has a high translational potential in treating or preventing hepatic injury associated with oxidative stress, inflammation and steatosis. This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Blocking the CCL2-CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model.

Hepatocellular carcinoma, a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand 2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in hepatocellular carcinoma patients. Here, we examined the therapeutic efficacy of CCL2-CCR2 axis inhibitors against hepatitis and hepatocellular carcinoma in the miR-122 knockout (a.k.a. KO) mouse model. This mouse model displays upregulation of hepatic CCL2 expression, which correlates with hepatitis that progress to hepatocellular carcinoma with age. Therapeutic potential of CCL2-CCR2 axis blockade was determined by treating KO mice with a CCL2-neutralizing antibody (nAb). This immunotherapy suppressed chronic liver inflammation in these mice by reducing the population of CD11highGr1+ inflammatory myeloid cells and inhibiting expression of IL6 and TNFα in KO livers. Furthermore, treatment of tumor-bearing KO mice with CCL2 nAb for 8 weeks significantly reduced liver damage, hepatocellular carcinoma incidence, and tumor burden. Phospho-STAT3 (Y705) and c-MYC, the downstream targets of IL6, as well as NF-κB, the downstream target of TNFα, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. In addition, CCL2 nAb enhanced hepatic NK-cell cytotoxicity and IFNγ production, which is likely to contribute to the inhibition of tumorigenesis. Collectively, these results demonstrate that CCL2 immunotherapy could be an effective therapeutic approach against inflammatory liver disease and hepatocellular carcinoma. Mol Cancer Ther; 16(2); 312-22. ©2016 AACR.

8-bromo-7-methoxychrysin Reversed M2 Polarization of Tumor-associated Macrophages Induced by Liver Cancer Stem-like Cells.

Hepatocellular carcinoma (HCC) is related to chronic liver inflammation. M2 polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment promotes liver cancer stem-like cell (LCSLC) self-renewal capability and carcinogenicity. Therefore, reversing M2 polarization of TAMs could be an effective approach to cure HCC. To evaluate whether 8-bromo-7-methoxychrysin (BrMC) has an effect on M2 polarization of TAMs. LCSLC and conditional medium were obtained by sphere forming assay. Identification of LCSLC were analyzed by sphere forming, wound-healing and invasion assay. TAM and effects of BrMC on it were validated by immunofluorescence staining, ELISA and griess assay. Expressions of cancer stem cell and macrophage marker were analyzed by western blotting. Our results showed that BrMC significantly suppressed the expression of the M2 macrophage marker CD163. Furthermore, BrMC influenced the secretion profile of cytokines of TAMs. Mechanistically, BrMC reversed M2 polarization of TAMs due to inhibition of NF-κB activation. BrMC may be a potentially novel flavonoid agent that can be applied for disrupting the interaction of LCSLCs and TAMs.

Liver inflammation and fibrosis.

Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in the United States. Hepatocyte steatosis is a component of metabolic syndrome and insulin resistance. Hepatic steatosis may be benign or progress to hepatocyte injury and the initiation of inflammation, which activates immune cells. While Kupffer cells are the resident macrophage in the liver, inflammatory cells such as infiltrating macrophages, T lymphocytes, neutrophils, and DCs all contribute to liver inflammation. The inflammatory cells activate hepatic stellate cells, which are the major source of myofibroblasts in the liver. Here we review the initiation of inflammation in the liver, the liver inflammatory cells, and their crosstalk with myofibroblasts.

Effect of new direct-acting antiviral drugs on insulin resistance and glycemic control after treatment of chronic hepatitis C virus infection in type 2 diabetic patients

Background Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. The benefits of eradicating HCV infection with direct-acting antiviral (DAAs) may go well beyond avoiding the damage caused by chronic liver inflammation, to include declines in glycated hemoglobin percent and other metabolic parameters. The present study was designed to evaluate the effect of new DAAs drugs, used for treatment of HCV, on insulin resistance and glycemic control at the end of treatment and 3 months after end of treatment of HCV infection in patient with type 2 diabetic mellitus (T2DM) in Damietta Governorate. Patients and methods This study included 75 T2DM patients with chronic HCV infection. Patients were divided according to level of glycosylated hemoglobin percent into three groups. All patients received DAAs and were monitored by A1C%, homeostasis model assessment-insulin resistance, and fasting blood sugar before, at the end of treatment, and 12 week after the end of treatment. Patients were allocated into two groups: the first group included 57 (76%) patients with improved glycemic control (IGC) and the second group included 18 (24%) patients with nonimproved glycemic control (NIGC). Results In IGC group, 45 (78.9%) patients needed to decrease the dose of antidiabetic treatment. There were no significant differences between IGC and NIGC groups regarding sex and liver condition. The percentage of patients with old age, those with positive family history of T2DM, and those with long duration of T2DM were significantly higher in NIGC group compared with IGC. Conclusion Diabetic patients receiving DAAs should be closely monitored during reduction of antidiabetic drugs, especially regarding insulin and sulfonylurea, to avoid hypoglycemic events. Improvement of glycemic control with DAAs is seen more in younger patients without family history of T2DM and short duration of diabetes mellitus.

Hepatocellular Carcinoma and Possible Chemical and Biological Causes: A Review.

The development of hepatocellular carcinoma (HCC) is a multistep process. In HCC, progressive and morphologically distinct preneoplastic lesions/alterations associated with chronic liver injury, inflammation, hepatocellular degeneration/regeneration, necrosis, and small-cell dysplasia can be observed. The incidence of HCC exhibits regional and ethnic differences. Several cytotoxic and DNA-damaging chemicals are suggested to be the underlying causes of HCC-for example, acrylamide, perfluorooctanoic acid (PFOA), polychlorinated biphenyls (PCBs), benzo(a)pyrene (BaP), perfluorinated chemicals (PFCs), vinyl chloride monomer (VCM), and dietary contaminants (aflatoxins, ochratoxins). Also suggested are substances of abuse (alcohol) and biological agents, such as hepatitis B and C and human immunodeficiency virus 1 (HIV-1). These can act through genetic and/or epigenetic mechanisms. This review will shortly address the genetic and epigenetic mechanisms of HCC and focus on cytotoxic and DNA-damaging chemicals and biological agents, exposure to which are suggested to lead to HCC initiation, promotion, and/or progression.

Probiotics and Chronic Liver Diseases

Probiotics and Chronic Liver Diseases

Mesenchymal Stem Cell-Dependent Modulation of Liver Diseases.

Acute liver failure and cirrhosis display sequential and overlapping severe pathogenic processes that include inflammation, hepatocyte necrosis, and fibrosis, carrying a high mortality rate. Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells with immunonodulatory characteristics. MSCs are considered to act through multiple mechanisms to coordinate a dynamic, integrated response to liver inflammation and fibrosis, which prevents the progressive distortion of hepatic architecture. Accordingly, MSCs as well as their products have been investigated as a novel therapeutic approach for the treatment of inflammatory and fibrotic liver diseases.In this review, we highlight the current findings on the MSC-based modulation of liver inflammation and fibrosis, and the possible use of MSCs in the therapy of immune-mediated liver pathology. We briefly describe the cellular and molecular mechanisms involved in MSC-dependent modulation of cytokine production, phenotype and function of liver infiltrated inflammatory cells and compare effects of engrafted MSCs versus MSC-generated conditioned medium (MSC-CM) in the therapy of acute liver injury. In order to elucidate therapeutic potential of MSCs and their products in modulation of chronic liver inflammation and fibrosis, we present the current findings regarding pathogenic role of immune cells in liver fibrosis and describe mechanisms involved in MSC-dependent modulation of chronic liver inflammation with the brief overview of on-going and already published clinical trials that used MSCs for the treatment of immune mediated chronic liver diseases. The accumulating evidence shows that MSCs had a significant beneficial effect in the treatment of immune-mediated liver diseases.

Liver 5-HT7 receptors: A novel regulator target of fibrosis and inflammation-induced chronic liver injury in vivo and in vitro

Background and aimHepatocellular cancer (HCC) is the sixth most common cancer and liver fibrosis is strongly associated with HCC. Treatment options are limited, and preventive strategies should be developed. An important step in the beginning of liver fibrosis is a strong inflammatory response. 5-HT7 is the last recognized member of the serotonin receptor family and is expressed in both central nerve system and peripheral system and have a lot of functions like learning, memory, smooth muscular relaxation, in the control of circadian rhythms and thermoregulation, pain and migraine, schizophrenia, anxiety, cognitive disturbances, and even inflammation. MethodsWe therefore examined the biochemical, histopathological and molecular effects of the 5-HT7 receptor agonist and antagonist on inflammatory liver fibrogenesis in animal models of progressive cirrhosis: a mouse model induced by carbon tetrachloride (CCl4) and in Hep3b cells. Results5-HT7 expression was observed in the liver in vivo and in vitro in CCl4-induced damage. 5-HT7 receptor agonist but not the antagonist reduced liver markers in mice and in Hep3b cells in carbon tetrachloride (CCl4) induced damage. 5-HT7 agonist, but not antagonist, protected liver tissue from oxidative stress in fibrosis. 5-HT7 agonist but not antagonist induces anti-inflammatory, anti-fibrinotic and anti-cytokine features in liver fibrosis in vivo and in vitro. Conclusions5-HT7 receptors have modulatory function and are an up-and-coming pharmacological target in the inflammatory fibrotic process. 5-HT7 receptor agonist LP-44 showed significant hepatoprotective effects against liver fibrosis, and LP-44 might become a useful therapeutic target for chronic liver inflammation and fibrosis.

DJ-1 promotes development of DEN-induced hepatocellular carcinoma and proliferation of liver cancer cells.

Chronic liver inflammation and injuries play a critical role in development of hepatocellular carcinoma (HCC). Parkinson disease (autosomal recessive, early onset) 7, encoding PARK7 protein (also called DJ-1), plays important roles in many carcinogenesis processes and is essential in modulating inflammation. However, whether DJ-1 is involved in HCC development remains largely unknown. To determine the effect of DJ-1 on HCC development, we accessed the correlation of hepatic DJ-1 expression with overall survival (OS) and TNM stage in 96 HCC patients and found a significant inverse correlation between DJ-1 expression and OS. By adopting a classic diethylnitrosamine (DEN)-induced murine HCC model, DJ-1 knockout (KO) mice displayed reduced tumorigenesis and cell proliferation, accompanied by decreased hepatic inflammation and IL-6/STAT3 activation. Furthermore, after an acute DEN challenge, DJ-1 KO mice showed significant decreases in liver injury, hepatocyte proliferation and DNA damage. In a human HCC cell line (MHCC-97L), cancer cell proliferation was induced by overexpression of DJ-1 and is related to oncogenic signaling of MAPKs and AKT. Induction of DJ-1 may serve as a novel regulator for HCC cell proliferation and HCC development possibly through enhanced MAPK signaling and inflammation.

Functional role of CCL5/RANTES for HCC progression during chronic liver disease

During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development. CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMOΔhepa/CCL5-/- animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24h or 8weeks. In CLD patients, CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2-/- and NEMOΔhepa model. CCL5 deletion in NEMOΔhepa mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45+/Ly6G+ granulocytes, CD45+/CD11b+/Gr1.1+/F4/80+ pro-inflammatory monocytes, CD4+ and CD8+ T cells were decreased. One year old NEMOΔhepa/CCL5-/- mice displayed smaller and less malignant tumors, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as the main source of CCL5, while CCL5 deficiency did not sensitise NEMOΔhepa hepatocytes towards TNFα induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8weeks ameliorated liver disease progression. We identified an important role of CCL5 in human and functionally in mice with disease progression, especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD. Our present study identifies the essential role of the chemoattractive cytokine CCL5 for liver disease progression and especially hepatocellular carcinoma development in men and mice. Finally, the inhibition of CCL5 appears to be encouraging for therapy of human chronic liver disease.

FAKTOR- FAKTOR YANG MEMENGARUHI BIDAN DALAM PEMBERIAN IMUNISASI HEPATITIS B PADA BAYI BARU LAHIR DI WILAYAH KERJA PUSKESMAS PANCUR BATU TAHUN 2015

Hepatitis B is a liver disease caused by hepatitis B virus (VHB), a family member of Hepadnavirus that can cause chronic liver inflammation and may progress to liver cirrhosis. The prevalence of hepatitis B in Indonesia is still high due to transmission of hepatitis B disease from mother to childbirth. Goals : The purpose of this research is to know the factors influencing the midwife in giving Hepatitis B immunization to newborn in Pancur Batu Puskesmas Working Area. Methods : The type of research is survey with cross sectional data measurement method. The population is all mothers in the working area of Pancur Batu Community Health Center September 2015 assisted by 102 midwives, the entire population is sampled. Data analysis was done by univariate test, Chi Square and multiple logistic regression. Result : The results showed that motivation (p = 0.046, 95% CI 1.016-5,882), ability (p = 0,019, 95% CI 1,195-7,034) and midwife perception (p = 0,044; 95% CI 1,025-5,949) influence immunization Hepatitis B. The most influential variable is the ability with the value Exp B = 2.899 means that midwives who have good ability have an opportunity to provide hepatitis B immunization 2,899 times greater than the midwife with poor ability. The low coverage of immunization is due to approximately 64.7% of mothers saying the midwife did not explain to the mother that all newborns should be given this hepatitis B immunization, 59.2% of mothers said they did not get an explanation from the midwife about the benefits of hepatitis B immunization in infants, and 59.8% of mothers said they did not know that the first hepatitis B immunization given to infants should not pass from seven days after the baby was born so they thought hepatitis B immunization could be given when the baby was more than 1 month old. Conclution : It is advisable to Pancur Batu Puskesmas to further increase the coverage of hepatitis B immunization by increasing the role of mothers to bring their children immunization, and conduct training for all health workers. Give awards for midwives to motivate themselves more in carrying out their duties.

The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development

Autoimmune hepatitis (AIH) is defined as a chronic liver inflammation with loss of tolerance against hepatocytes. The etiology and pathophysiology of AIH are still poorly understood because reliable animal models are limited. Therefore, we recently introduced a model of experimental murine AIH by a self-limited adenoviral infection with the AIH type 2 antigen formiminotransferase cyclodeaminase (FTCD).We could demonstrate that break of humoral tolerance towards liver specific autoantigens like FTCD and cytochrome P450 2D6 (CYP2D6) is not dependent on the genetic background. However, the development of AIH in autoantibody positive animals is determined by genetic background genes. We could also show that the break of humoral tolerance is necessary but not sufficient for the development of AIH. In contrast the break of tolerance against the ubiquitously expressed nuclear antigens (ANAs) is strictly dependent on genetic predisposition. Priming with the UGA suppressor tRNA-associated protein (soluble liver antigen; SLA) is a strong inducer of ANA reactivity, but not sufficient to cause AIH development thereby questioning the importance of anti-SLA immune response as an important driver in AIH. Monogenetic mutations such as Aire-deficiency can cause AIH in otherwise genetically resistant strains. ConclusionThe results have important implications for our understanding of the pathophysiology of AIH development and for the interpretation of humoral antibody responses in AIH.

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis.

Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.

Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers fibrosis-4 score and aspartate aminotransferase-platelet ratio index.

Novel direct antiviral agents (DAA) targeting hepatitis C virus (HCV) have revolutionized the treatment of chronic hepatitis C infection (CHC). Rates of sustained virological response (SVR) to treatment have drastically improved since introduction of DAA. Transient Elastography (TE) is an ultrasound based, non-invasive technique to assess liver stiffness (LS). We examined the changes in TE values and fibrosis scores FIB-4 and APRI after DAA treatment of CHC. 549 patients who received a DAA based treatment for CHC were screened and 392 were included. TE values recorded prior to therapy and within 18months after therapy were evaluated. In addition, FIB-4 and APRI scores were calculated and histopathological results were recorded if available. Median TE prior to DAA treatment was 12.65kPa (IQR 9.45-19.2kPa) and decreased to 8.55kPa (IQR 5.93-15.25) post-treatment. This finding is statistically significant (P<.001) and equals a TE regression of 32.4% after DAA treatment. Median FIB-4 and APRI values significantly decreased from 2.54 (IQR 1.65-4.43) and 1.10 (IQR 0.65-2.43) to 1.80 (IQR 1.23-2.84, P<.001) and 0.43 (IQR 0.3-0.79, P<.001) respectively. Patients with SVR after DAA therapy showed significant regression of TE values. Rapid decrease in TE was in concordance with regression of validated fibrosis scores FIB-4 and APRI. It remains to be examined whether this indicates a true regression of fibrosis or merely resolution of chronic liver inflammation with subsequent improvement of TE values and laboratory parameters.

Liver regeneration and fibrosis after inflammation.

The liver is a unique organ with an extraordinary capacity to regenerate upon various injuries. In acute and transient liver injury by insults such as chemical hepatotoxins, the liver in rodents returns to the original architecture by proliferation and remodeling of the remaining cells within a week. In contrast, chronic liver inflammation due to various etiologies, e.g., virus infection and metabolic and immune disorders, results in liver fibrosis, often leading to cirrhosis and carcinogenesis. In both acute and chronic inflammation, a variety of immune and non-immune cells in the liver is involved in the processes resulting in either regeneration or fibrosis. In addition, chronic hepatitis often accompanies proliferation of atypical biliary cells, also known as liver progenitor cells or oval cells. Although the origin of liver progenitor cells and its contribution to hepatic repair is still under intense debate, recent studies have revealed a regulatory role for immune cells in progenitor proliferation and differentiation. In this review, we summarize recent studies on liver regeneration and fibrosis in the viewpoint of inflammation.

Fas Receptor Activation by Endogenous Opioids Is A New Mechanism for Cardiomyopathy in Cirrhotic Rats

Cirrhosis, a common consequence of chronic liver inflammation is associated with various cardiovascular dysfunctions which are called cirrhotic cardiomyopathy (CC). Among the various possible causes of CC, apoptosis is considered to have a pivotal role. To explore the contribution of endogenous opioids in the apoptosis process in a rat model of CC. Four genes were selected to cover both intrinsic and extrinsic pathways of apoptosis. Cardiac samples from 4 groups of rats were evaluated. Two groups were cirrhotic through bile duct ligation (BDL) receiving either naltrexone (BDL-naltrexone) or saline (BDL-saline), two others were normal rats as sham groups receiving either naltrexone (sham-naltrexone) or saline (sham-saline). Expression level of BCL2, Caspase3, Fas and FasL was explored in all groups using reverse transcriptase real-time PCR. BDL-saline group showed significant over-expression of BCL2, caspase3 and Fas. BCL2 expression was 1.44 (P<0.001) and caspasse3 was 1.35 (P<0.001) times higher than sham-saline group, Fas was also overexpressed 1.3 (P<0.001) times higher than BDL-naltrexone group and 1.91 (P<0.001) compared to sham-naltrexone group. Caspase3 expression was 1.35 (P<0.001) folds higher than sham-naltrexone group. The expression pattern of FasL revealed no statistically significant change among study groups. Fas molecule enrollment during CC is a novel finding. Fas molecule is activated during cirrhosis through elevated levels of endogenous opioids. This pathway is one of the leading causes of CC. Our findings also demonstrated the protective role of naltrexone as opioids antagonist on cardiomyocytes in a rat model of CC.

In silico analysis of Hepatitis C virus (HCV) polyprotein domains and their comparison with other pathogens and allergens to gain insight on pathogenicity mechanisms

Hepatitis C (HCV) is a deadly virus from family Flaviviridae, causing acute or chronic liver inflammation. Given its lethality and no known vaccine to curb it, understanding its pathogenic mechanism is critical. By analyzing the domains in its protein sequence, a plethora can be learnt about its immune manipulation strategies. In this regard, current in silico study compares publicly-available HCV polyprotein sequences and their domain profiles. Apart from using UniProt sequences and SMART (Simple modular architecture research tool) platform for domain profiling, a set of customized scripts were developed to extract the patterns of protein domain distribution. Also, the total domain set in representative HCV polyprotein sequences were compared with that of other viral pathogens (Ebola, HIV, Dengue, Zika) and allergens (plant pollen, cockroach allergens) to find the conserved domains of key role in pathogenesis.

Dual Roles of IFN-γ and IL-4 in the Natural History of Murine Autoimmune Cholangitis: IL-30 and Implications for Precision Medicine.

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease with a long natural history. The pathogenesis of PBC is thought to be orchestrated by Th1 and/or Th17. In this study, we investigated the role of CD4+ helper T subsets and their cytokines on PBC using our previous established murine model of 2-OA-OVA immunization. We prepared adeno-associated virus (AAV)-IFN-γ and AAV-IL-4 and studied their individual influences on the natural history of autoimmune cholangitis in this model. Administration of IFN-γ significantly promotes recruitment and lymphocyte activation in the earliest phases of autoimmune cholangitis but subsequently leads to downregulation of chronic inflammation through induction of the immunosuppressive molecule IL-30. In contrast, the administration of IL-4 does not alter the initiation of autoimmune cholangitis, but does contribute to the exacerbation of chronic liver inflammation and fibrosis. Thus Th1 cells and IFN-γ are the dominant contributors in the initiation phase of this model but clearly may have different effects as the disease progress. In conclusion, better understanding of the mechanisms by which helper T cells function in the natural history of cholangitis is essential and illustrates that precision medicine may be needed for patients with PBC at various stages of their disease process.

Immune mechanisms in chronic viral hepatitis

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are the major causes of chronic liver inflammation worldwide. Although both viruses induce immune-mediated acute and chronic inflammatory liver diseases, the natural history and outcome of HBV and HCV infections are different. This is because of both viruses and host features, like genetic, immunologic and environmental. Hereby, we present the immune mechanisms and immunopathogenesis involved in chronic viral hepatitis. Keywords: HBV, HCV, Innate immunity, Adaptive immunity