Different Types Of Interferon Research Articles

Interferon therapy and its association with depressive disorders - A review.

Interferons (IFNs) are important in controlling the innate immune response to viral infections. Besides that, studies have found that IFNs also have antimicrobial, antiproliferative/antitumor and immunomodulatory effects. IFNs are divided into Type I, II and III. Type I IFNs, in particular IFN-α, is an approved treatment for hepatitis C. However, patients developed neuropsychological disorders during treatment. IFN-α induces proinflammatory cytokines, indoleamine 2,3-dioxygenase (IDO), oxidative and nitrative stress that intensifies the body's inflammatory response in the treatment of chronic inflammatory disease. The severity of the immune response is related to behavioral changes in both animal models and humans. Reactive oxygen species (ROS) is important for synaptic plasticity and long-term potentiation (LTP) in the hippocampus. However, excess ROS will generate highly reactive free radicals which may lead to neuronal damage and neurodegeneration. The limbic system regulates memory and emotional response, damage of neurons in this region is correlated with mood disorders. Due to the drawbacks of the treatment, often patients will not complete the treatment sessions, and this affects their recovery process. However, with proper management, this could be avoided. This review briefly describes the different types of IFNs and its pharmacological and clinical usages and a focus on IFN-α and its implications on depression.

Comparative In Silico Analysis and Functional Characterization of TANK-Binding Kinase 1-Binding Protein 1.

Protein modelling plays a vital role in the drug discovery process. TANK-binding kinase 1-binding protein 1 is also called an adapter protein, which is encoded by gene TBK1 present in Homo sapiens. It is found in lungs, small intestine, leukocytes, heart, placenta, muscle, kidney, lower level of thymus, and brain. It has a number of protein-binding sites, to which TBK1 and IKBKE bind and perform different functions as immunomodulatory, antiproliferative, and antiviral innate immunity which release different types of interferons. Our study predicts the comparative model of 3-dimensional (3D) structure through different bioinformatics tools that will be helpful for further studies in future. The reactivity and stability of these proteins were evaluated physicochemically and through domain determination and prediction of secondary structure using bioinformatics methods such as ProtParam, Pfam, and SOPMA, respectively. Robetta, an ab initio approach, I-TASSER, and AlphaFold was used for 3D structure prediction, and the models were validated using the SAVESv6.0 (PROCHECK) server. Conclusively, the best 3D structure of TBK1-binding protein 1 was predicted using Robetta software. After unveiling the 3D structure of the novel protein, we concluded that this structure will help us to find out its role other than in antiviral innate immunity and by producing torsion in its 3D structure researchers will be able to detect either this protein is involved in any disease or not because according to previous studies it was not associated with any disease.

Dysregulated Interferon Response and Immune Hyperactivation in Severe COVID-19: Targeting STATs as a Novel Therapeutic Strategy.

A disease outbreak in December 2019, caused by a novel coronavirus SARS-CoV-2, was named COVID-19. SARS-CoV-2 infects cells from the upper and lower respiratory tract system and is transmitted by inhalation or contact with infected droplets. Common clinical symptoms include fatigue, fever, and cough, but also shortness of breath and lung abnormalities. Still, some 5% of SARS-CoV-2 infections progress to severe pneumonia and acute respiratory distress syndrome (ARDS), with pulmonary edema, acute kidney injury, and/or multiple organ failure as important consequences, which can lead to death. The innate immune system recognizes viral RNAs and triggers the expression of interferons (IFN). IFNs activate anti-viral effectors and components of the adaptive immune system by activating members of the STAT and IRF families that induce the expression of IFN-stimulated genes (ISG)s. Among other coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, common strategies have been identified to antagonize IFN signaling. This typically coincides with hyperactive inflammatory host responses known as the “cytokine storm” that mediate severe lung damage. Likewise, SARS-CoV-2 infection combines a dysregulated IFN response with excessive production of inflammatory cytokines in the lungs. This excessive inflammatory response in the lungs is associated with the local recruitment of immune cells that create a pathogenic inflammatory loop. Together, it causes severe lung pathology, including ARDS, as well as damage to other vulnerable organs, like the heart, spleen, lymph nodes, and kidney, as well as the brain. This can rapidly progress to multiple organ exhaustion and correlates with a poor prognosis in COVID-19 patients. In this review, we focus on the crucial role of different types of IFN that underlies the progression of SARS-CoV-2 infection and leads to immune cell hyper-activation in the lungs, exuberant systemic inflammation, and multiple organ damage. Consequently, to protect from systemic inflammation, it will be critical to interfere with signaling cascades activated by IFNs and other inflammatory cytokines. Targeting members of the STAT family could therefore be proposed as a novel therapeutic strategy in patients with severe COVID-19.

Characterization of the temporal, cell-specific and interferon-inducible patterns of indoleamine 2,3 dioxygenase 1 (IDO1) expression in the human placenta across gestation.

The human placenta performs multiple functions necessary for successful pregnancy, but the metabolic pathways and molecular mechanisms responsible for regulating placental development and functions remain incompletely understood. Catabolism of the essential amino acid tryptophan has numerous critical roles in normal physiology, including inflammation. The kynurenine pathway, which accounts for ∼90% of tryptophan breakdown, is mediated by indoleamine 2,3 dioxygenase 1 (IDO1) in the placenta. In pregnant mice, alterations of IDO1 activity or expression result in fetal resorption and a preeclampsia-like phenotype. Decreased IDO1 expression at the maternal-fetal interface has also been linked to preeclampsia, in utero growth restriction and recurrent miscarriage in humans. These collective observations suggest essential role(s) for IDO1 in maintaining healthy pregnancy. Despite these important roles, the precise temporal, cell-specific and inflammatory cytokine-mediated patterns of IDO1 expression in the human placenta have not been thoroughly characterized across gestation. Western blot and whole mount immunofluorescence (WMIF) were utilized to characterize and quantify basal and interferon (IFN)-inducible IDO1 expression in 1st trimester (7-13 weeks), 2nd trimester (14-22 weeks) and term (39-41 weeks) placental villi. IDO1 expression is activated in the human placenta between the 13th and 14th weeks of pregnancy, increases through the 2nd trimester and remains elevated at term. Constitutive IDO1 expression is restricted to placental endothelial cells. Interestingly, different types of IFNs have distinct effects on IDO1 expression in the human placenta. Our collective results are consistent with potential role(s) for IDO1 in the regulation of vascular functions in placental villi.

Off balance: Interferons in COVID-19 lung infections.

Interferons are innate and adaptive cytokines involved in many biological responses, in particular, viral infections. With the final response the result of the balance of the different types of Interferons. Cytokine storms are physiological reactions observed in humans and animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules. The excessive and prolonged presence of these cytokines can cause tissue damage, multisystem organ failure and death. The role of Interferons in virus clearance, tissue damage and cytokine storms are discussed, in view of COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The imbalance of Type I, Type II and Type III Interferons during a viral infection contribute to the clinical outcome, possibly together with other cytokines, in particular, TNFα, with clear implications for clinical interventions to restore their correct balance.

Sharpening up tumor microenvironment to enhance the efficacy of immune checkpoint blockade on head and neck cancer using a CpG-oligodeoxynucleotide

Head and neck cancers are a type of life-threatening cancers characterized by an immunosuppressive tumor microenvironment. Only less than 20% of the patients respond to immune checkpoint blockade therapy, indicating the need for a strategy to increase the efficacy of immunotherapy for this type of cancers. Previously, we identified a type B CpG-oligodeoxynucleotide (CpG-ODN) called CpG-2722, which has the universal activity of eliciting an immune response in grouper, mouse, and human cells. In this study, we further characterized and compared its cytokine-inducing profiles with different types of CpG-ODNs. The antitumor effect of CpG-2722 was further investigated alone and in combination with an immune checkpoint inhibitor in a newly developed syngeneic orthotopic head and neck cancer animal model. Along with other inflammatory cytokines, CpG-2722 induces the gene expressions of interleukin-12 and different types of interferons, which are critical for the antitumor response. Both CpG-2722 and anti-programmed death (PD)-1 alone suppressed tumor growth. Their tumor suppression efficacies were further enhanced when CpG-2722 and anti-PD-1 were used in combination. Mechanistically, CpG-2722 shaped a tumor microenvironment that is favorable for the action of anti-PD-1, which included promoting the expression of different cytokines such as IL-12, IFN-β, and IFN-γ, and increasing the presence of plasmacytoid dendritic cells, M1 macrophages, and CD8 positive T cells. Overall, CpG-2722 provided a priming effect for CD8 positive T cells by sharpening the tumor microenvironment, whereas anti-PD-1 released the brake for their tumor-killing effect, resulting in an enhanced efficacy of the combined CpG-2722 and anti-PD-1.

English

Since December 2019, COVID-19 disease caused by SARS-CoV-2 virus has spread world-wide as pandemic causing large number of infected persons and lot of deaths of COVID patients. There is currently no definite medicine for treatment of the disease as well as any preventive measure. With the progress of multiplication of viruses in the human, activation and amplification of host immune response take place causing massive release of varieties of cytokines like interleukin (IL)-1, IL-6, IL-17, etc., and different types of interferons (IFNs), tumour necrosis factor (TNF) to form cytokine storm. From studies of COVID-19 patients in hospital, it has also been noted that uncontrolled inflammation due to elevated levels of cytokine (cytokine storm) is responsible for causing severity of the disease. In this article the properties of cytokine, types of cytokine and other details have been discussed. The mechanism of signalling of cytokine to immunity and the reason for causing cytokine storm with its role in causing fatalities in COVID 19 patients have also been pointed out. Low infection of virus persists in upper airway that causes similar to seasonal respiratory illness but with severe infections virus remains in the lower respiratory tract leading to lung injury, acute respiratory distress syndrome (ARDS) and sometimes death. The role of cytokine storm in causing severity of disease has been discussed. Key words: Cytokine, IL-6, IL-17, IL-33 families, signalling mechanism, immunity, cytokine storm, role in COVID-19.

IRF-1, RIG-I and MDA5 display potent antiviral activities against norovirus coordinately induced by different types of interferons

Norovirus represents the main cause of acute nonbacterial gastroenteritis worldwide. In immunocompromised patients, it bears high risk of causing chronic infection with significant morbidity and mortality. The lack of specific treatment prompts the development of anti-norovirus agents. In this study, we have investigated the role of interferon (IFN) response and evaluated antiviral activities of different IFNs against human norovirus (HuNoV) replication using a HuNoV replicon model. We found that HuNoV RNA replication was sensitive to all types of IFNs, including IFNα (type I), IFNγ (type II), IFNλ1 and 3 (type III). IFNs canonically induce interferon-stimulated genes (ISGs) to exert their antiviral activities. By profiling a subset of important human ISGs using an overexpression approach, we have identified RTP4 and HPSE as moderate anti-norovirus ISGs, whereas IRF-1, RIG-I (also known as DDX58) and MDA5 (also known as IFIH1) were identified as potent anti-norovirus effectors. Interestingly, type I and III IFNs coordinately induced IRF-1, RIG-I and MDA5; whereas type II IFN predominantly induced IRF-1 to exhibit their anti-norovirus activities. Combination of different IFNs revealed that IFNγ worked cooperatively with type I or type III IFNs to induce ISGs and subsequently inhibit HuNoV replication. Of note, replication of HuNoV did not interfere with antiviral IFN response. In summary, we showed the potent anti-norovirus activities of different types of IFNs and identified the key anti-norovirus effectors. These findings are important for understanding norovirus-host interactions and developing antiviral therapies.

Quality of life among hepatitis C patients on treatment, Minia, Egypt

Background: Hepatitis C is a highly prevalent infectious disease among Egyptian population. Different types of interferon and antiviral drugs are used in the treatment and have significant side effects which may alter quality of life of the treated chronic hepatitis C patients. The aim of the study was to identify the course of and factors associated with HRQOL in HCV patients given standard treatment based and to assess its relation to socio-demographic and clinical characteristics.Methods: This prospective consecutive hospital based study included 120 chronic hepatitis C patients in El-Minia city and by using SF-36V2 questionnaire.Results: HRQOL baseline scores, general health had the lowest score, followed by vitality, while Role emotional had the highest score. Physical component summery scores (PCS) was slightly higher than mental component summery scores (MCS) for PCS. Subjects showed significantly lower SF-36 scores at the 12th week of treatment Compared to the pretreatment values. Mean scores of all SF-36 domains improved by the end of treatment, (p<0.01). Scales most affected during therapy were vitality (VT), general health (GH) and bodily pain (BP). The effect size (ES) observed on SF-36 subscales, the most affected dimensions at the 12th week of treatment were (PF, SF, VT and BP) (they were ≥0.8) could be considered large change, according to Cohen’s criteria.Conclusions: Subjects showed significantly lower SF-36 scores at the 12th week of treatment. Mean scores of all SF-36 domains improved by the end of treatment.

The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block.

ABSTRACTType I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFN-γ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-γ stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-γ-sensitive/resistant viruses indicates that interferon resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted by env and is therefore mediated by unknown IFN-γ-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission.IMPORTANCE The human immune system can hinder invading pathogens through interferon (IFN) signaling. One consequence of this signaling is that cells enter an antiviral state, increasing the levels of hundreds of defenses that can inhibit the replication and spread of viruses. The majority of HIV-1 infections result from a single virus particle (the transmitted/founder) that makes it past these defenses and colonizes the host. Thus, the founder virus is hypothesized to be a relatively interferon-resistant entity. Here, we show that certain HIV-1 envelope genes have the unanticipated ability to resist specific human defenses mediated by different types of interferons. Strikingly, the envelope gene from a founder HIV-1 virus is far better at evading these defenses than the corresponding gene from a common HIV-1 lab strain. Thus, these defenses could play a role in constraining the transmission of HIV-1 and may select for transmitted viruses that are resistant to this IFN-mediated inhibition.

Balance between IL-3 and type Iinterferons and their interrelationship with FasL dictates lifespan and effector functions of human basophils.

In contrast to eosinophils and neutrophils, the regulation of the lifespan of human basophils is poorly defined, with the exception of the potent anti-apoptotic effect of IL-3 that also promotes pro-inflammatory effector functions and phenotypic changes. Type I IFNs (IFN-α, IFN-β), which are well known for their anti-viral activities, have the capacity to inhibit allergic inflammation. To elucidate whether type I IFNs have the potential to abrogate the lifespan and/or effector functions of human basophils. We cultured human basophils, and for comparison, eosinophils and neutrophils, with IL-3, interferons, FasL and TRAIL, alone or in combination, and studied cell survival, effector functions and signalling pathways involved. Despite an identical pattern of early signalling in basophils, eosinophils and neutrophils in response to different types of interferons, only basophils displayed enhanced apoptosis after type I IFN treatment. IFN-γ prolonged survival of eosinophils but did not affect the lifespan of basophils. IFN-α-mediated apoptosis required STAT1-STAT2 heterodimers and the contribution of constitutive p38 MAPK activity. Whereas the death ligands FasL and TRAIL-induced apoptosis in basophils per se, IFN-α-mediated apoptosis did neither involve autocrine TRAIL signalling nor did it sensitize basophils to FasL-induced apoptosis. However, IFN-α and FasL displayed an additive effect in killing basophils. Interestingly, IL-3, which protected basophils from IFN-α-, TRAIL- or FasL-mediated apoptosis, did not completely block the additive effect of combined IFN-α and FasL treatment. Moreover, we demonstrate that IFN-α suppressed IL-3-induced release of IL-8 and IL-13. In contrast to IFN-α-mediated apoptosis, these inhibitory effects of IFN-α were not dependent on p38 MAPK signalling. Our study defines the unique and granulocyte-type-specific inhibitory and pro-apoptotic function of type I IFNs and their cooperation with death ligands in human blood basophils, which may be relevant for the anti-allergic properties of type I IFNs.

Low-density lipoprotein receptor genetic polymorphism in chronic hepatitis C virus Egyptian patients affects treatment response.

To correlate a genetic polymorphism of the low-density lipoprotein (LDL) receptor with antiviral responses in Egyptian chronic hepatitis C virus (HCV) patients. Our study included 657 HCV-infected patients with genotype 4 who received interferon-based combination therapy. Patients were divided into two groups based on their response to therapy: 356 were responders, and 301 were non-responders. Patients were compared to 160 healthy controls. All patients and controls underwent a thorough physical examination, measurement of body mass index (BMI) and the following laboratory tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total bilirubin, direct bilirubin, prothrombin time, prothrombin concentration, INR, complete blood count, serum creatinine, fasting blood sugar, HCV antibody, and hepatitis B surface antigen. All HCV patients were further subjected to the following laboratory tests: HCV-RNA using quantitative polymerase chain reaction (PCR), antinuclear antibodies, thyroid-stimulating hormone, an LDL receptor (LDLR) genotype study of LDLR exon8c.1171G>A and exon10c.1413G>A using real-time PCR-based assays, abdominal ultrasonography, ultrasonographic-guided liver biopsy, and histopathological examination of liver biopsies. Correlations of LDL receptor polymorphisms with HAI, METAVIR score, presence of steatosis, and BMI were performed in all cases. There were no statistically significant differences in response rates between the different types of interferon used or LDLR exon10c.1413G>A. However, there was a significant difference in the frequency of the LDL receptor exon8c.1171G>A genotype between cases (AA: 25.9%, GA: 22.2%, GG: 51.9%) and controls (AA: 3.8%, GA: 53.1% and GG: 43.1%) (P < 0.001). There was a statistically significant difference in the frequency of the LDLR exon 8C:1171 G>A polymorphism between responders (AA: 3.6%, GA: 15.2%, GG: 81.2%) and non-responders (AA: 52.2%, GA: 30.6%, GG: 17.2%) (P < 0.001). The G allele of LDL receptor exon8c.1171G>A predominated in cases and controls over the A allele, and a statistically significant association with response to interferon was observed. The frequency of the LDLR exon8c.1171G>A allele in non-responders was: A: 67.4% and G: 32.6 vs A: 11.2% and G: 88.8% in responders (P < 0.001). Therefore, carriers of the A allele exhibited a 16.4 times greater risk for non-response. There was a significant association between LDL receptors exon8 c.1171G>A and HAI (P < 0.011). There was a significant association between LDL receptors exon8c.1171G>A and BMI. The mean BMI level was highest in patients carrying the AA genotype (28.7 ± 4.7 kg/m(2)) followed by the GA genotype (28.1 ± 4.8 kg/m(2)). The lowest BMI was the GG genotype (26.6 ± 4.3 kg/m(2)) (P < 0.001). The only significant associations were found between LDL receptors exon8 c.1171G>A and METAVIR score or steatosis (P < 0.001). LDL receptor gene polymorphisms play a role in the treatment response of HCV and the modulation of disease progression in Egyptians infected with chronic HCV.

Hepatology highlights

Hepatology highlights

Effects of different types of interferon on the expression of HCV replication-related microRNA

To explore the effects of different types of interferon (IFN) on the expression of hepatitis C virus(HCV) replication-related miRNAs in human hepatocytes. The levels of miRNAs in Huh7 cells treated with types I (IFN-α, IFN-β), II (IFN-γ) and III (IFN-λ1) interferons (IFNs) were determined by real-time quantitative polymerase chain reaction (PCR). The levels of various miRNAs were compared among different IFN treatment groups. The expression of miRNA-196, miRNA-296, miRNA-351, miRNA-431 and miRNA-448 in IFN-α, IFN-β and IFN-λ1 treated groups was higher than that in control group (474.5 ± 57.7, 436.0 ± 37.8, 431.3 ± 43.5 vs 99.5 ± 2.4; 389.5 ± 44.0, 416.3 ± 36.7, 284.8 ± 20.9 vs 99.0 ± 0.8; 453.3 ± 51.1, 473.8 ± 24.0, 522.0 ± 40.3 vs 99.5 ± 2.1; 288.3 ± 44.9, 294.3 ± 29.9, 450.0 ± 29.5 vs 100.5 ± 2.4; 319.0 ± 35.4, 357.0 ± 27.5, 446.5 ± 61.2 vs 99.8 ± 1.0; all P < 0.05). The expression of miRNA-196, miRNA-351 and miRNA-448 in IFN-γ-treated group (271.3 ± 29.6, 140.5 ± 27.5, 177.8 ± 23.4) was higher than that in control group (all P < 0.05). But the expression of miRNA-431 and miRNA-296 had no significant difference between IFN-γ treated group and control group (both P > 0.05). The expression of miRNA-122 at difference concentrations (10, 100, 1 000 U/ml) of IFN-α, IFN-β, IFN-γ and IFN-λ1 (10, 100, 1 000 ng/ml) was lower than that in control group (49.3 ± 4.9, 32.0 ± 3.7, 24.5 ± 3.7 vs 99.5 ± 2.1; 53.5 ± 1.9, 35.5 ± 2.7, 25.8 ± 4.0 vs 98.8 ± 1.3; 60.8 ± 7.1, 43.8 ± 4.0, 33.5 ± 4.2 vs 99.3 ± 2.6; 50.0 ± 2.9, 35.5 ± 3.3, 22.3 ± 3.8 vs 100.3 ± 1.5; all P < 0.01). Different types of IFN increase the expression of miRNAs that inhibit HCV replication and decrease the expression of miRNA-122 that supports HCV replication. Thus the regulation of HCV replication-related miRNA expression is a general anti-HCV mechanism by different types of IFN. However, the regulation pattern by type II IFN is different from those by other types of IFNs, implying that type II IFN has different anti-HCV mechanisms from other types of IFN at miRNA level.

Toll-like receptor-activated primary human hepatocytes produce inflammatory cytokines and different types of interferon, resulting in HCV suppression in a co-culture model

Toll-like receptor-activated primary human hepatocytes produce inflammatory cytokines and different types of interferon, resulting in HCV suppression in a co-culture model

Toll-like receptor-activated primary human hepatocytes produce inflammatory cytokines and different types of interferon, resulting in HCV suppression in vitro

Aims: The function of the hepatic innate immune system and its role in the defence against Hepatitis C Virus infection is not well understood. Recent publications suggested that type-III interferons (IFN; Interleukin 28A, –28B and –29) play a crucial role in the host response against HCV. Aim of this study was to investigate the Toll-like receptor (TLR) signaling in primary human hepatocytes and the capacity of these cells to produce type-III IFNs and their ability to control HCV replication. Methods: Human liver samples were obtained after tumor resection (n=16) or liver transplantation (n=14). Human hepatocytes (n=30) were isolated after perfusion and digestion of the liver. Cells were stimulated with TLR1–9 ligands for 6–24h, expression of Tumor necrosis factor α (TNF-α), Interleukin 6 (IL–6), IL–10, IFN-α, -β, -γ and –λ were determined by qRT-PCR and ELISA. Gene expression of interferon sensitive genes (ISGs) was determined by qRT-PCR. Results: In human hepatocytes stimulation with TLR1–9 ligands, except TLR9, led to cell-type specific induction of pro-inflammatory (TNF-α, IL–6) and anti-inflammatory cytokines (IL–10). In contrast, expression of type-I, -II and –III interferons (IFN-α, -β, -γ, IL–28A, IL–28B, IL–29) could only be induced after TLR3 stimulation, resulting in enhanced expression of ISGs (ISG15, IFI-T1, RSAD2, MXA). Therefore, HCV replication was only suppressed after co-culture of supernatants from TLR3-activated hepatocytes with a subgenomic HCV replicon. The different underlying diseases, the type of surgery, fibrosis stage as well as liver function tests (ALT, AST, GGT, AP) did not correlate with TLR signaling and antiviral activity in these cells. Conclusion: Primary isolated human hepatocytes respond to TLR ligands by production of pro-inflammatory (TNF-α and IL6) anti-inflammartory (IL–10) cytokines as well as type-I, -II and –III IFN. This results in induction of antiviral ISGs and subsequent suppression of HCV replication i n vitro.

Sequence variability at the internal ribosome entry site of the HCV genome in relation to therapy outcome

Different types of interferon are widely used to treat hepatitis C virus (HCV) infection. Results obtained in vitro suggest that interferon inhibits internal ribosome entry site (IRES)-mediated translation of the HCV genome. To elucidate the possible effect of the nucleotide sequence of IRES on therapy outcome, we compared HCV isolates from patients with sustained response and non-response to interferon/ribavirin combination therapy. In 56 analyzed HCV isolates, nucleotide changes appeared strictly in the stem-loop IIIb region, the stem part from 243 nt to 248 nt, and the polypyrimidine-II region. The natural sequence variability of IRES in isolates of genotype 3a was significantly higher than in isolates of genotype 1b (p &lt; 0.05). The average number of nucleotide changes in genotype 3a correlated with response to therapy (p &lt; 0.05).

Cell-specific but p53-independent Regulation of Vascular Endothelial Growth Factor Expression by Interferons in Human Glioblastoma Cells

Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Interferons (IFNs) have been widely used in the treatment of malignant or recurrent gliomas with only marginal benefit. The association between IFNs and VEGF expression remains unclear and should be an intensively investigated subject. The present study therefore examined the effects of different types of IFNs on VEGF expression in human T98G, A172 and U251 glioblastoma cells by quantitative RT-PCR and ELISA. Both type I (alpha, beta) and type II (gamma) IFNs upregulated VEGF expression in a cell-specific but p53-independent manner. Actinomycin D experiments demonstrated that IFNs did not alter VEGF mRNA stability. In contrast, induction of VEGF mRNA by IFNs was blocked by the protein synthesis inhibitor cycloheximide. Interestingly, cycloheximide also blocked IFN-induced activation of the p44/p42 mitogen-activated protein kinase, which was partially required for induction of VEGF by IFNs. These findings suggest that VEGF might be an indirect target gene of IFNs, and might provide insights into therapeutic applications of IFNs against angiogenesis-dependent tumors.

Interferons upregulate thymidine phosphorylase expression via JAK-STAT-dependent transcriptional activation and mRNA stabilization in human glioblastoma cells

Overexpression of the angiogenic enzyme thymidine phosphorylase (TP) in tumor cells and/or infiltrating macrophages correlates with increased microvessel density and poor prognosis in various tumor types including glioma. The present study examined how the TP gene expression is regulated by different types of interferons (IFNs) in human T98G and A172 glioblastoma cells. Both type I (alpha, beta) and type II (gamma) IFNs upregulated TP mRNA and protein expression while inhibiting cell proliferation. IFN-induced TP mRNA accumulation was not inhibited by the protein synthesis inhibitor cycloheximide, but was strongly blocked by the transcription inhibitor actinomycin D, as well as by transcription factor decoy oligodeoxynucleotides containing the putative IFN response element or the gamma-activated sequence in the TP promoter. The Janus kinase (JAK) inhibitor AG-490 blocked both IFN-induced STAT1 (signal transducers and activators of transcription 1) phosphorylation and TP expression. All IFNs increased the stability of TP mRNA as well. In addition, IFN-evoked TP enzyme activity enhanced the cytotoxicity of 5-fluorouracil (5-FU). These findings indicate that TP expression may be upregulated by IFNs via the JAK-STAT signaling pathway and both transcriptional and posttranscriptional mechanisms. Combined treatment with IFN and 5-fluorouracil may be a useful therapeutic strategy for malignant gliomas.

Predictive value of twenty-four-hour quantification in interferon therapy of chronic hepatitis C using different types of interferon

Predictive value of twenty-four-hour quantification in interferon therapy of chronic hepatitis C using different types of interferon