transforming-growth-factor-beta and Hepatitis--Autoimmune

Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8

Topics: Animals; CD8-Positive T-Lymphocytes; Hepatitis, Autoimmune; Humans; Interleukin-10; Interleukin-2; Transforming Growth Factor beta; Transforming Growth Factors

Oxidative and nitrosative stresses can damage cellular membranes, disrupt mitochondrial function, alter gene expression, promote the apoptosis and necrosis of hepatocytes, and increase fibrosis in diverse acute and chronic liver diseases, including autoimmune hepatitis. The objectives of this review are to describe the mechanisms of oxidative and nitrosative stresses in inflammatory liver disease, indicate the pathogenic implications of these stresses in autoimmune hepatitis, and suggest investigational opportunities to develop interventions that counter them. The principal antioxidant defenses, including glutathione production, the activities of antioxidant enzymes, and the release of the nuclear factor erythroid 2-related factor 2, may be inadequate or suppressed by transforming growth factor beta. The generation of reactive oxygen species can intensify nitrosative stress, and this stress may not be adequately modulated by the thioredoxin-thioredoxin reductase system and induce post-translational modifications of proteins that further disrupt hepatocyte function. The unfolded protein response and autophagy may be unable to restore redox stability, meet metabolic demands, and maintain hepatocyte survival. Emerging interventions with highly selective site- and organelle-specific actions may improve outcomes, and they include inhibitors of nicotinamide adenine dinucleotide phosphate oxidase, nitric oxide synthase, and transforming growth factor beta. Pharmacological manipulation of nuclear transcription factors may favor expression of antioxidant genes, and stimulation of chaperone proteins within the endoplasmic reticulum and modulation of autophagy may prevent hepatic fibrosis and enhance cell survival. These interventions constitute investigational opportunities to improve the management of autoimmune hepatitis.

Topics: Antioxidants; Autophagy; Glutathione; Hepatitis, Autoimmune; Hepatocytes; Humans; Liver; Mitochondria, Liver; NADPH Oxidases; NF-E2 Transcription Factor; Nitric Oxide Synthase; Nitrosation; Oxidative Stress; Protein Processing, Post-Translational; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase; Thioredoxins; Transforming Growth Factor beta; Unfolded Protein Response

Hepatic fibrosis develops or progresses in 25 % of patients with autoimmune hepatitis despite corticosteroid therapy. Current management regimens lack reliable noninvasive methods to assess changes in hepatic fibrosis and interventions that disrupt fibrotic pathways. The goals of this review are to indicate promising noninvasive methods to monitor hepatic fibrosis in autoimmune hepatitis and identify anti-fibrotic interventions that warrant evaluation. Laboratory methods can differentiate cirrhosis from non-cirrhosis, but their accuracy in distinguishing changes in histological stage is uncertain. Radiological methods include transient elastography, acoustic radiation force impulse imaging, and magnetic resonance elastography. Methods based on ultrasonography are comparable in detecting advanced fibrosis and cirrhosis, but their performances may be compromised by hepatic inflammation and obesity. Magnetic resonance elastography has excellent performance parameters for all histological stages in diverse liver diseases, is uninfluenced by inflammatory activity or body habitus, has been superior to other radiological methods in nonalcoholic fatty liver disease, and may emerge as the preferred instrument to evaluate fibrosis in autoimmune hepatitis. Promising anti-fibrotic interventions are site- and organelle-specific agents, especially inhibitors of nicotinamide adenine dinucleotide phosphate oxidases, transforming growth factor beta, inducible nitric oxide synthase, lysyl oxidases, and C-C chemokine receptors types 2 and 5. Autoimmune hepatitis has a pro-fibrotic propensity, and noninvasive radiological methods, especially magnetic resonance elastography, and site- and organelle-specific interventions, especially selective antioxidants and inhibitors of collagen cross-linkage, may emerge to strengthen current management strategies.

Topics: Adrenal Cortex Hormones; Antioxidants; Apoptosis; CCR5 Receptor Antagonists; Cytokines; Elasticity Imaging Techniques; Extracellular Matrix; Hepatitis, Autoimmune; Humans; Inflammation; Liver Cirrhosis; Magnetic Resonance Imaging; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Protein-Lysine 6-Oxidase; Receptors, CCR2; Severity of Illness Index; Transforming Growth Factor beta; Vitamin D Deficiency

Although several mouse models of AIH have been described, no model is ideal. Indeed, the disease is self-limited in each model, and none is associated with significant liver fibrosis or progression to cirrhosis. Nevertheless, these models should be useful for testing different hypotheses regarding the initiation of AIH. Still, each model poses unique limitations. The EAIH model initiated by immunization with crude liver antigens in CFA has been plagued by a high prevalence of hepatitis lesions in CFA controls and inconsistencies in results. The TGF beta-1 and IL-2 deficient models lead to high in utero mortality and short median life spans in the surviving animals. Lastly, all models require more detailed characterization of the antigen specificity of infiltrating liver T cells and the pathogenesis of liver cell injury.

Topics: Animals; Autoantigens; Autoimmunity; Disease Models, Animal; Genetic Predisposition to Disease; Hepatitis, Autoimmune; Humans; Immune Tolerance; Interleukin-2; Mice; Mice, Inbred Strains; Mice, Knockout; Rats; Transforming Growth Factor beta

In experimental autoimmune hepatitis (EAH) of Th1 profile, an extract of adult Ascaris suum worms (ASC) was previously found to deviate the immune response to a Th2/IL-10 pattern. Here, the effects of treatment with ASC on production of TGF-β and the anti-Ascaris isotypes IgG1 and IgG2a in EAH were evaluated. EAH was induced in BALB/c mice, intravenously with concanavalin A. Two hours later, these animals received ASC (EAH+ASC group) or PBS vehicle (EAH group). IgG1 and IgG2a were evaluated 8 h, 24 h and 7 d after induction. TGF-β was measured in a splenocyte culture at this last time. The isotype levels in the EAH group were low throughout the kinetics. In the EAH+ASC group, there was significant production of IgG1 at 24 h and 7 d, but of IgG2a only at 7 d. There was statistically greater production of TGF-β in the EAH+ASC group. The higher levels of IgG1 and TGF-β in this group suggest that an additional Th1 response control route exists in EAH, which needs to be investigated.

Topics: Animals; Antibodies, Helminth; Antigens, Helminth; Ascaris suum; Disease Models, Animal; Hepatitis, Autoimmune; Immunoglobulin G; Male; Mice; Mice, Inbred BALB C; Transforming Growth Factor beta

Autoimmune hepatitis is a chronic immune-mediated liver injury caused by dysregulated immune response to liver antigens. Genetic susceptibility is affected by multiple single nucleotide polymorphisms in immune-related genes. There are few reports on the association of TGF-β and IL-10 genetic variants with autoimmune hepatitis.. Allele frequency and genotype status of IL-10 -1082, -819, -592 and TGF-β +869 and +915 polymorphisms were investigated in 57 unrelated patients with autoimmune hepatitis and 140 healthy controls by polymerase chain reaction with sequence-specific primers.. IL-10 -592 and -819 allele frequencies and genotypes were not associated with autoimmune hepatitis in our population, while IL-10 -1082 genotypes were. IL-10 -1082/-819/-592 "high-producing" haplotype GCC was significantly less frequent in patients. TGF-β +869 "high-producing" allele C and genotype CC were significantly more in autoimmune hepatitis, compared to controls; whereas, TGF-β +915 "low-producing" allele C and genotype CC were significantly more in autoimmune hepatitis compared to control. TGF-β +869/+915 haplotype TG was significantly less frequent in patients while CC haplotype was significantly more frequently observed in patients.. We identified a significant association between IL-10 -1082/-819 and TGF-β +869/+915 genotypes and haplotypes with autoimmune hepatitis in Iranians.

Topics: Child; Female; Gene Frequency; Genotype; Haplotypes; Hepatitis, Autoimmune; Humans; Interleukin-10; Iran; Male; Polymorphism, Single Nucleotide; Transforming Growth Factor beta

We here report a 47-year-old female with autoimmune myelofibrosis (AIMF) associated with liver damage caused by autoimmune hepatitis and Evans syndrome. Bone marrow biopsy revealed hypocellular marrow with grade 2 reticulin fibrosis and increased levels of B lymphocytes (CD20

Topics: Anemia, Hemolytic, Autoimmune; Bone Marrow; Drug Resistance; Female; Hepatitis, Autoimmune; Humans; Middle Aged; Prednisolone; Primary Myelofibrosis; Rituximab; Thrombocytopenia; Transforming Growth Factor beta

To investigate the preventive and therapeutic effects of rapamycin (RAPA) on autoimmune hepatitis and liver fibrosis induced by concanavalin A (ConA) and possible mechanisms.. Female C57BL/6 mice aged 8 weeks were randomly divided into normal control group, ConA model group, and ConA+RAPA treatment group. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured; hematoxylin-eosin and Masson staining and Knodell HAI and Ishak scoring systems were used to evaluate the degrees of liver inflammation and fibrosis. Gradient centrifugation was used to separate mononuclear cells, flow cytometry was used to measure CD4(+)/CD8(+) ratio, and intracellular cytokine staining was performed to measure the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor β (TGF-β) in immune cells. The t-test was used for data comparison between groups.. The RAPA treatment group showed a significant reduction in serum ALT level compared with the ConA model group (P < 0.05). Liver inflammatory injury was reduced significantly, and there was no obvious fibrous tissue proliferation. The level of TGF-β in mononuclear cells was reduced significantly, and the treatment group had a significantly lower level of TGF-β than the model group (8.91%±1.25% vs 16.65%±2.05%, P < 0.05). The proportions of CD4(+) and CD8(+)T cells in the liver were reduced, and the treatment group had significantly lower proportions of CD4(+) and CD8(+)T cells than the model group (proportion of CD4(+)T cells: 4.09%±1.20% vs 8.91%±0.69%, P < 0.05; proportion of CD8(+)T cells: 3.28%±0.66% vs 9.68%±1.46%, P < 0.05). The proportion of Th1 cells was reduced, and the treatment group had a significantly lower proportion of Th1 cells than the model group (1.02%±0.06% vs 2.83%±0.21%, P < 0.05); the proportions of Th3 and Tr1 regulatory T cells were increased, and the treatment group had significantly higher proportions of Th3 and Tr1 regulatory T cells than the model group (proportion of Th3 regulatory T cells: 59.53%±9.82% vs 47.13%±4.79%, P < 0.05; proportion of Tr1 regulatory T cells: 10.63%±2.27% vs 7.09%±1.66%, P < 0.05), but the proportion of Th2 cells showed no significant difference between the two groups (P > 0.05).. RAPA can promote the differentiation of Th3/Tr1 cells, reduce the expression of TGF-β in mononuclear cells, slow down the progression of chronic hepatitis induced by ConA into liver fibrosis, and thus prevent liver fibrosis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Concanavalin A; Female; Hepatitis, Autoimmune; Interferon-gamma; Interleukin-10; Interleukin-4; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Random Allocation; Sirolimus; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Reactive oxygen species (ROS) play a key role in chronic liver injury and fibrosis. Homologs of NADPH oxidases (NOXs) are major sources of ROS, but the exact role of the individual homologs in liver disease is unknown. Our goal was to determine the role of NOX4 in liver fibrosis induced by bile duct ligation (BDL) with the aid of the pharmacological inhibitor GKT137831, and genetic deletion of NOX4 in mice. GKT137831 was either applied for the full term of BDL (preventive arm) or started at 10 day postoperatively (therapeutic arm). Primary hepatic stellate cells (HSC) from control mice with and without BDL were analyzed and the effect of NOX4 inhibition on HSC activation was also studied. FasL or TNFα/actinomycin D-induced apoptosis was studied in wild-type and NOX4(-/-) hepatocytes. NOX4 was upregulated by a TGF-β/Smad3-dependent mechanism in HSC. Downregulation of NOX4 decreased ROS production and the activation of NOX4(-/-) HSC was attenuated. NOX4(-/-) hepatocytes were more resistant to FasL or TNFα/actinomycin D-induced apoptosis. Similarly, after pharmacological NOX4 inhibition, ROS production, the expression of fibrogenic markers, and hepatocyte apoptosis were reduced. NOX4 was expressed in human livers with stage 2-3 autoimmune hepatitis. Fibrosis was attenuated by the genetic deletion of NOX4. BDL mice gavaged with GKT137831 in the preventive or the therapeutic arm displayed less ROS production, significantly attenuated fibrosis, and decreased hepatocyte apoptosis. In conclusion, NOX4 plays a key role in liver fibrosis. GKT137831 is a potent inhibitor of fibrosis and hepatocyte apoptosis; therefore, it is a promising therapeutic agent for future translational studies.

Topics: Animals; Apoptosis; Bile Ducts; Dactinomycin; Fas Ligand Protein; Gene Deletion; Hepatic Stellate Cells; Hepatitis, Autoimmune; Hepatocytes; Humans; Ligation; Liver; Liver Cirrhosis; Mice; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 4; NADPH Oxidases; Pyrazoles; Pyrazolones; Pyridines; Pyridones; Rats; Reactive Oxygen Species; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

We previously reported that paediatric (PAH) and adult (AAH) forms of type I autoimmune hepatitis (AH) have different HLA-associations and clinical outcome. In the present study we investigated the role of TGF-beta1 genetic polymorphisms in the different outcome of PAH and AAH. We found a significant increase of "high producer" 25GG genotype in PAH and 10CC in AAH. Low inflammation and low fibrosis in AAH was associated with the increase of codon 10CC (high producer) and codon 25CC (low producer) genotypes. The analysis in AAH of the two positions-haplotypes revealed that combined presence of 25GG and 10CC seems to neutralize the 10CC effect which remained in AAH having the 10CC(+)-25GG(-) haplotype. Altogether these results may explain, at least partially, the different clinical outcome of AAH and PAH.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Alleles; Child; Child, Preschool; Codon; DNA; Female; Genotype; Hepatitis, Autoimmune; Humans; Infant; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Young Adult

Participation of Tregs in the generation of autoimmune hepatic inflammation (AHI) was examined using a newly established dendritic cell (DC)-based mouse model of hepatitis. The inflammatory activity of AHI peaked 21 days after DC vaccination. Forkhead box P3 (Foxp3) expression on day 21 was significantly increased in the liver but was decreased in the spleen. CD4(+)CD25(+) Tregs from the liver on day 21 showed inhibitory activity against the proliferation of CD4(+)CD25(-) T cells. On day 21, the expression of CXCR3 on Tregs and its ligand CXCL9 in hepatic tissue was upregulated, and levels of mRNA of transforming growth factor (TGF)-beta and IL-2, essential for Treg differentiation, in the liver were also increased. Suppression of AHI activity by prednisolone treatment decreased Treg accumulation in the liver. Accumulation of Tregs might occur through Treg recruitment mediated by CXCR3/CXCL9 interaction and expansion in the liver by upregulated TGF-beta and IL-2.

Topics: Animals; Cell Proliferation; Chemokine CXCL9; Dendritic Cells; Female; Flow Cytometry; Forkhead Transcription Factors; Hepatitis, Autoimmune; Immunoblotting; Immunohistochemistry; Interleukin-2; Mice; Mice, Inbred C57BL; Receptors, CXCR3; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Transforming growth factor beta (TGFbeta) promotes hepatocellular apoptosis and suppresses hepatic lymphocyte responses in part through activation of Smad3. The purpose of the current study was to determine the importance of Smad3 signaling in an experimental model of autoimmune hepatitis induced by concanavalin A (ConA), a process involving T cell activation and hepatocellular apoptosis. C57Bl/6 wild-type (Wt) or Smad3-deficient (Smad3(-/-)) mice were injected intravenously with 15 mg/kg ConA or vehicle. Nine hours post ConA injection, Wt mice presented with severe hepatitis as assessed by increased liver transferases. This injury was associated with eosinophil accumulation and preceded at 3 hours post-injection by significant increases in hepatic T helper 1 (interferon gamma) and T helper 2 (interleukin-4) cytokine production. Absence of Smad3 significantly blunted hepatocellular injury 9 hours post ConA injection, which was associated with reduced early T helper 1 and T helper 2 cytokine production and eosinophil accumulation. Smad3(-/-) livers also showed significant reductions in hepatocellular apoptosis as assessed by terminal UTP nick-end labeling when compared to ConA-treated Wt mice in conjunction with reduced caspase 3 cleavage, which was likely mediated by a Smad3-dependent inhibition of the survival factor extracellular signal-regulated kinase 1/2. In vitro, Smad3(-/-) hepatocytes were resistant to TGFbeta-induced apoptosis, and this protection was dependent on extracellular signal-regulated kinase activation.. Together, these results show, for the first time, the significance of Smad3 signaling in autoimmune hepatitis, underlining the control of Smad3-dependent TGFbeta signaling on proinflammatory cytokine production, eosinophil recruitment, and hepatocellular apoptosis. Interruption of this pathway could be beneficial clinically to limit acute fulminant liver pathologies.

Topics: Animals; Apoptosis; Caspase 3; Cell Survival; Concanavalin A; Cytokines; Eosinophils; Extracellular Signal-Regulated MAP Kinases; Hepatitis, Autoimmune; Hepatocytes; Injections; Liver; Lymphocyte Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Smad3 Protein; T-Lymphocytes; Transforming Growth Factor beta

We have reported quantitative and qualitative differences in bone marrow (BM) progenitor cells in autoimmune hepatitis type-1 (AIH-1) and primary biliary cirrhosis (PBC). This study investigated the apoptotic features and cytokine suppressors of haematopoiesis in long-term cultures of BM mononuclear cells (BMMCs) from AIH-1 and PBC patients.. Apoptotic markers and CD14 expression were evaluated in 13 AIH-1 patients, 13 PBC patients, 12 cirrhotic controls and 10 healthy subjects. TNF-alpha, TGF-beta and IFN-gamma were determined using ELISAs.. All apoptotic markers and CD14 were increased in AIH-1 and PBC compared to controls (P<0.0001). Fas+ cells were positively correlated (P=0.0001) with apoptotic cells in AIH-1 and PBC. TNF-alpha and IFN-gamma were higher in AIH-1 (P=0.003 and P=0.001) and PBC (P=0.0001) compared to controls. No differences were found between the control groups.. We demonstrate for the first time that the apoptotic process, macrophage activation and the production of cytokine suppressors of haematopoiesis in BMMCs from AIH-1 and PBC patients are higher compared to controls. The Fas-FasL pathway is likely to be involved in the apoptotic process; the increased levels of selected cytokines may contribute to Fas-FasL stimulation. Cirrhosis appears unlikely to be the cause of the above findings.

Topics: Adult; Aged; Apoptosis; Biomarkers; Bone Marrow Cells; Cell-Free System; Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis, Autoimmune; Humans; Interferon-gamma; Leukocytes, Mononuclear; Liver Cirrhosis, Biliary; Male; Middle Aged; Reference Values; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

In autoimmune hepatitis, strong TGF-beta1 expression is found in the inflamed liver. TGF-beta overexpression may be part of a regulatory immune response attempting to suppress autoreactive T cells. To test this hypothesis, we determined whether impairment of TGF-beta signaling in T cells leads to increased susceptibility to experimental autoimmune hepatitis (EAH). Transgenic mice of strain FVB/N were generated expressing a dominant-negative TGF-beta type II receptor in T cells under the control of the human CD2 promoter/locus control region. On induction of EAH, transgenic mice showed markedly increased portal and periportal leukocytic infiltrations with hepatocellular necroses compared with wild-type mice (median histological score = 1.8 +/- 0.26 vs. 0.75 +/- 0.09 in wild-type mice; P < 0.01). Increased IFN-gamma production (118 vs. 45 ng/ml) and less IL-4 production (341 vs. 1,256 pg/ml) by mononuclear cells isolated from transgenic livers was seen. Impairment of TGF-beta signaling in T cells therefore leads to increased susceptibility to EAH in mice. This suggests an important role for TGF-beta in immune homeostasis in the liver and may teleologically explain TGF-beta upregulation in response to T cell-mediated liver injury.

Topics: Animals; B-Lymphocytes; Blotting, Northern; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Hepatitis, Autoimmune; Homeostasis; Immunohistochemistry; Mice; Mice, Transgenic; Neutrophil Infiltration; Phenotype; Signal Transduction; T-Lymphocytes; Transforming Growth Factor beta

Transforming growth factor-beta1 (TGF-beta1) is considered the most important mediator of hepatic fibrogenesis. At the same time, TGF-beta1 is an immunosuppressive cytokine. Development of fibrosis, often rapid, is a characteristic of autoimmune hepatitis, as is spontaneous systemic immunosuppression. The aim of our study was therefore to define the role of TGF-beta1 in autoimmune hepatitis.. Using the MV 1Lu bioassay, we found markedly elevated serum levels of TGF-beta1 (median 109 ng/ml) in active autoimmune hepatitis, which normalised when patients reached biochemical remission following immunosuppressive therapy (median 34 ng/ml; p=0.0001 compared to active disease). With a newly established ELISPOT-assay for TGF-beta1-producing cells, we could exclude an increase in TGF-beta1-producing peripheral blood cells as a source of the elevated TGF-beta1. However, by in situ hybridisation and immunohistochemistry, we found strong TGF-beta1 expression in the inflamed liver. In addition to non-parenchymal and infiltrating cells, many hepatocytes showed strong staining for TGF-beta1. TGF-beta1 expression in the liver normalised in remission, yet was still somewhat increased in patients with biochemical remission but remaining histological disease activity.. These results suggest that TGF-beta1 is an important mediator in active autoimmune hepatitis. They support the theory that immunosuppressive therapy needs to be guided by histology, as prevention of the development of cirrhosis presumably requires near complete suppression of TGF-beta1 in the liver; this is only found when there is no longer any histological evidence of inflammation.

Topics: Adolescent; Adult; Aged; Biological Assay; Biomarkers; Female; Hepatitis, Autoimmune; Humans; Immunohistochemistry; In Situ Hybridization; Inflammation; Liver; Male; Middle Aged; Monocytes; Transforming Growth Factor beta