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Inhibitory effects of interferons on pancreatic stellate cell activation

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World Journal of Gastroenterology 2006年第6期12卷 896-901页

作者： Jan-TidoBaumert GiselaSparmann J rgEmmrich StefanLiebe RobertJaster Department of Me-dicine Division of GastroenterologyMedical FacultyUniversity of RostockE-Heydemann-Str.618057 Rostock Germany

AIM： To analyze and to compare the effects of interferon （IFN）-α, IFN-β, and IFN-γ on pancreatic stellate cell （PSC） activation/n vitro and to elucidate the molecular basis of IFN action. METHODS： PSCs were isolated from rat＇s pancreatic tissue, cultured and stimulated with recombinant rat IFNs. Cell proliferation and collagen synthesis were assessed by measuring the incorporation of 5-bromo-2＇ -deoxyuridine （BrdU） into DNA and [^3H]-proline into acetic acid-soluble proteins, respectively. Apoptotic ceils were determined by FACS analysis （sub-G1 peak method）. Exhibition of the myofibroblastic PSC phenotype was monitored by immunoblot analysis of （α-smooth muscle actin （α-SMA） expression. To assess the activation of signal transducer and activator of transcription （STAT）, Western blots using phospho- STAT-specific antibodies were performed. In studies on STAT1 function, expression of the protein was inhibited by siRNA. RESULTS： IFN-β and IFN-γ, but not IFN-α significantly diminished PSC proliferation and collagen synthesis. IFN-γ, was the only IFN that clearly inhibited α-SMA expression. Under the experimental conditions used, no enhanced rate of apoptotic cell death was observed in response to any IFN treatment. IFN-β and IFN-γ, induced a strong increase of STAT1 and STAT3 tyrosine phosphorylation, while the effect of IFN-α was much weaker. Inhibition of STAT1 expression with siRNA was associated with a significantly reduced growth-inhibitory effect of IFN-γ. CONCLUSION： IFN-β and particularly IFN-γ, display inhibitory effects on PSC activation in vitro and should be tested regarding their in vitro efficiency. Growth inhibition by IFN-γ action requires STAT1.

关键词： interferons Pancreatic stellate cell Apoptosis

Toll-like receptors and hepatitis C virus infection

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Hepatobiliary & Pancreatic Diseases International 2021年第6期20卷 521-529页

作者： Yang Gao Narayan Nepal Shi-Zhu Jin Department of Gastroenterology and Hepatology The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086China

Background:Hepatitis C virus(HCV)infection is a worldwide ***,the current treatment for hepatitis C has many ***-like receptors(TLRs)are pattern recognition receptors involved in HCV infection,and an increasing number of studies are focusing on the role of TLRs in the progression of hepatitis *** sources:We performed a Pub Med search up to January 2021 with the following keywords:hepatitis C,toll-like receptors,interferons,inflammation,and immune *** also used terms such as single-nucleotide polymorphisms(SNPs),susceptibility,fibrosis,cirrhosis,direct-acting antiviral agents,agonists,and antagonists to supplement the query *** reviewed relevant publications analyzing the correlation between hepatitis C and TLRs and the role of TLRs in HCV ***:TLRs 1–4 and 6–9 are involved in the process of HCV *** the host is exposed to the HCV,TLRs,as important participants in HCV immune evasion,trigger innate immunity to remove the virus and also promote inflammation and liver *** gene SNPs affect hepatitis C susceptibility,treatment,and *** contribution of each TLR to HCV is *** targeting various TLRs are developed and validated,and TLRs can synergize with classic hepatitis C drugs,including interferon and direct-acting antiviral agents,constituting a new direction for the treatment of hepatitis ***:TLRs are important receptors in HCV *** TLRs induce different mechanisms of virus clearance and inflammatory *** TLR-related antiviral therapy strategies exist,more studies are needed to explore the clinical application of TLR-related drugs.

关键词： Hepatitis C Toll-like receptors interferons Inflammation Immune evasion

RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis

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Virologica Sinica 2023年第5期38卷 741-754页

作者： Yue Si Haijun Zhang Ziqing Zhou Xudong Zhu Yongheng Yang He Liu Liang Zhang Linfeng Cheng Kerong Wang Wei Ye Xin Lv Xijing Zhang Wugang Hou Gang Zhao Yingfeng Lei Fanglin Zhang Hongwei Ma Department of Microbiology School of Basic MedicineAir Force Medical UniversityXi'an710032China Department of Neurology Xijing HospitalAir Force Medical UniversityXi'an710032China Center of Clinical Aerospace Medicine School of Aerospace MedicineKey Laboratory of Aerospace Medicine of Ministry of EducationAir Force Medical UniversityXi'an710032China Department of Anesthesiology&Critical Care Medicine Xijing HospitalAir Force Medical UniversityXi'an710032China The College of Life Sciences and Medicine Northwest UniversityXi'an710069China

Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)***,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains ***,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 ***-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral ***3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I ***,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV ***3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune ***,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase ***,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.

关键词： Hantaan virus(HTNV) RIPK3 interferons IFN-stimulated genes STAT1 Innate immune response

Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression

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Cellular & Molecular Immunology 2022年第10期19卷 1130-1140页

作者： Tihong Shao Patrick S.C.Leung Weici Zhang Koichi Tsuneyama William M.Ridgway Howard A.Young Zongwen Shuai Aftab A.Ansari M.Eric Gershwi Department of Rheumatology and Immunology The First Affiliated Hospital of Anhui Medical UniversityHefeiChina Division of Rheumatology Allergyand Clinical ImmunologySchool of MedicineUniversity of CaliforniaDavisCAUSA Department of Pathology and Laboratory Medicine Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan Center for Cancer Research National Cancer Institute-FrederickFrederickMDUSA

The interferon(IFN)signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of *** have generated a unique murine model named ARE-Del,with chronic overexpression of IFNγ,by altering IFNγ***,these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis,including high titers of autoantibodies and portal *** hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of *** study this hypothesis,ARE-Del^(+/−)mice were treated with the JAK1/2 inhibitor ruxolitinib and serially *** inhibition resulted in a significant reduction in portal inflammation and bile duct damage,associated with a significant reduction in splenic and hepatic CD4^(+)T cells and CD8^(+)T ***,ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγand TNF from splenic CD4^(+)T ***,ruxolitinib treatment also decreased the frequencies of germinal center B(GC B)cells and T follicular helper(Tfh)cells and led to lower serological AMA *** note,liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib ***,ruxolitinib inhibited the secretion of IL-6,TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro,indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 *** data highlight the significance,both immunologically and clinically,of the JAK/STAT signaling pathway in autoimmune cholangitis.

关键词： Primary biliary cholangitis Autoimmunity interferons Janus Kinase Inhibitors Ruxolitinib

Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B

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World Journal of Gastroenterology 2021年第14期27卷 1369-1391页

作者： Zhi Yi Goh Ee Chee Ren Hui Ling Ko Singapore Immunology Network Agency for ScienceTechnology and ResearchSingapore 138648Singapore Integrative Sciences and Engineering Programme NUS Graduate SchoolNational University of SingaporeSingapore 119077Singapore Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University of SingaporeSingapore 119260Singapore

250 million people worldwide continue to be chronically infected with the *** patients may be treated with nucleoside/nucleotide analogues,this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA(cccDNA)*** a result,HBV infection cannot be cured,and the virus reactivates when conditions are ***(IFNs)are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected *** have been shown to induce cccDNA clearance,but their use in the treatment of HBV infection is limited as HBVtargeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN ***,to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV,instead of direct IFN administration,novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be *** review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA *** include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic *** addition,the mechanisms that HBV employs to disrupt IFN signalling will be *** that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV ***,these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.

关键词： Covalently closed circular DNA interferons APOBECs Epigenetic modification Hepatitis B virus therapeutics

Revolution in the diagnosis and management of hepatitis C virus infection in current era

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World Journal of Hepatology 2022年第4期14卷 647-669页

作者： Farina M Hanif Zain Majid Nasir Hassan Luck Abbas Ali Tasneem Syed Muddasir Laeeq Muhammed Mubarak Department of Hepatogastroenterology Sindh Institute of Urology and TransplantationKarachi 74200SindhPakistan Department of Histopathology Sindh Institute of Urology and TransplantationKarachi 74200SindhPakistan

Chronic hepatitis C virus(HCV)infection is a major global public health problem,particularly in developing part of the *** advances have been made in the early diagnosis and treatment of the *** management has been particularly revolutionized during the past two *** this review,we summarize the major advances in the diagnostic and management armamentarium for chronic HCV *** focus of the present review is on the newer directly acting anti-viral agents,which have revolutionized the management of chronic HCV *** of uncomplicated chronic HCV infection and of specific complications and special at-risk populations of patients will be covered in *** the advent and approval of highly effective and well tolerable oral agents,still many challenges remain,particularly the affordability,the equitable distribution and access to later *** World Health Organization aims to eliminate viral hepatitis including HCV by 2030 since its poses a major public health *** is an urgent need to ensure uniform and early access to diagnostic and therapeutic facilities throughout the world if the later goal has to be realized.

关键词： Hepatitis C virus interferons Diagnosis Management Directly acting antiviral agents

Treatment of Hepatitis C in Patients Undergoing Immunosuppressive Drug Therapy

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Journal of Clinical and Translational Hepatology 2016年第3期4卷 206-227页

作者： Kohtaro Ooka Joseph K.Lim Department of Internal Medicine Yale University School of Medicine New Haven CT USA Yale Liver Center Section of Digestive Diseases Yale University School of Medicine New Haven CT USA

With 185 million people chronically infected globally,hepatitis C is a leading bloodborne ***-oral regimens of direct acting agents have superior efficacy compared to the historical interferon-based regimens and are significantly more ***,trials of both types of regimens have often excluded patients on immunosuppressive medications for reasons other than organ ***,these patients-most often suffering from malignancy or autoimmune diseases-could stand to benefit from these *** this study,we systematically review the literature on the treatment of hepatitis C in these neglected *** on patients with organ transplants is more robust and this literature is reviewed here *** systematic review produced 2273 unique works,of which 56 met our inclusion criteria and were used in our *** quality of data was low;only 3 of the 56 studies were randomized controlled *** virologic response was reported ***-containing regimens achieved this end-point at rates comparable to that in immunocompetent *** adverse effects and death were *** on all-oral regimens were sparse,but in the most robust study,rates of sustained virologic response were again comparable to immunocompetent individuals (40/41).Efficacy and safety of interferoncontaining regimens and all-oral regimens were similar to rates in immunocompetent individuals;however,there were few interventional *** large number of case reports and case series makes conclusions vulnerable to publication *** firm conclusions are challenging,given the dearth of high-quality studies,our results demonstrate that antiviral therapy can be safe and *** advent of all-oral regimens offers patients and clinicians greatly increased chances of cure and fewer side *** data reveal that these regimens may confer such benefits in immunosuppressed individuals as *** pr

关键词： MeSH termsHepatitis C/dt[drug therapy] interferons Direct acting antivirals Immunosuppressive agents Chemotherapy

Effect of pegylated interferon alpha 2b plus ribavirin treatment on plasma transforming growth factor-β1,metalloproteinase-1,and tissue metalloproteinase inhibitor-1 in patients with chronic hepatitis C

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World Journal of Gastroenterology 2005年第43期11卷 6833-6838页

作者： Robert Flisiak Jerzy Jaroszewicz Tadeusz W Lapiski Iwona Flisiak Danuta Prokopowiczi Department of Infectious Diseases Department of Dermatology and Venereology

AIM： To evaluate the effect of antiviral treatment on plasma levels of transforming growth factor-β1 （TGF-β1）, metalloproteinase 1 （MMP-1）, and tissue inhibitor of metaUoproteinase-1 （TIMP-1） in patients with chronic hepatitis C. METHODS： TGF-β1, MMP-1, and TIMP-1 plasma concentrations were measured by an enzyme immunoassay in 28 patients, during 48 wk of treatment with pegylated interferon-alpha 2b （PEG-IFN-α2b） plus ribavirin （RBV） and after 24 wk of follow-up. Patients were divided into two groups： responders （R） and non-responders （NR） related to achieved sustained virologic response. Normal values were evaluated in plasma samples of 13 healthy volunteers. RESULTS： Baseline plasma concentrations of TGF-β1 and TIMP-1 （30.9±3.7 and 1 506±61 ng/mL respectively） measured in all subjects significantly exceeded the normal values （TGF-β1： 18.3±1.6 ng/mL and TIMP-1： 1 102±67 ng/mL）. In contrast, pretreatment MMP-1 mean level （6.5±0.9 ng/mL） was significantly lower than normal values （11.9±0.9 ng/mL）. Response to the treatment was observed in 12 patients （43%）. TGF-β1 mean concentration measured during the treatment phase decreased to the control level in both groups. However at wk 72, values of NR patients increased and became significantly higher than in R group. TIMP-1 concentrations in R group decreased during the treatment to the level similar to normal. In NR group, TIMP-1 remained significantly elevated during treatment and follow-up phase and significant difference between both groups was demonstrated at wk 48 and 72. MMP-1 levels were significantly decreased in both groups at baseline. Treatment caused rise of its concentration only in the R group, whereas values in NR group remained on the level similar to baseline. Statistically significant difference between groups was noted at wk 48 and 72. CONCLUSION： These findings support the usefulness of TGF-β1, TIMP-1, and MMP-1 in the management of chronic hepatitis C. Elevated TIMP-1 and low MMP-1 plasma concentratio

关键词： HCV Hepatitis Liver interferons Fibrosis

Response of TT virus to IFN plus ribavirin treatment in patients with chronic hepatitis C

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World Journal of Gastroenterology 2004年第1期10卷 143-146页

作者： JavierMoreno RafaelBarcena SantosdelCampo GloriaMoraleda Mluisa Mateos Department of Gastroenterology Hospital Ramon y CajalFacultad de MedicinaUniversidad de AlcalaMadridSpain Department of Microbiology Hospital Ramon y CajalMadridSpain

AIM:TT virus (TTV) is a newly described DNA virus related to postransfusion hepatitis that produces persistent viremia in the absence of clinical ***-IFN plus ribavirin have been useful in the treatment of chronic hepatitis C *** study investigated the responses of TT virus (TTV) and hepatitis C virus (HCV) to PEG-IFN plus ribavirin therapy. METHODS:Fifteen patients infected with HCV were treated with PEG-IFN(0.5 μg/body weight/week) and ribavirin (1000 mg-1 200 mg/daily) for 48 weeks,Blood samples were drawn at the beginning and the end of the *** TTV DNA and HCV RNA were quantified by real time PCR. RESULTS:At the beginning of treatment,TTV infection was detected in 10/15 (66.6%) of HCV-infected *** of serum TTV DNA at the end of therapy occurred in 6/10 (60%) *** of these 6 patients,4 (67%) became positive for TTV DNA after 6 months of *** HCV viremia,11/15 (73%) patients were negative for serum HCV RNA after 48 weeks of therapy,7/11 (64%) of these cases also became negative for TTV DNA following the combined *** the 3/4 (75%) patients who were positive for HCV RNA at the end of therapy,TTV DNA was detected as *** HCV response at 6 months after treatment was 53% (8/15). CONCLUSION:No TTV sustained response can be achieved in any patient after PEG-IFN plus ribavirin administration.

关键词： Torque teno virus Adult Antiviral Agents dosage DNA Virus Infections Drug Therapy, Combination Female Hepatitis C, Chronic Humans interferons Male Middle Aged Research Support, Non-U.S. Gov't Ribavirin Treatment Outcome