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1
Bruening, Janina, Bettina Weigel, and Gisa Gerold. "The Role of Type III Interferons in Hepatitis C Virus Infection and Therapy." Journal of Immunology Research 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/7232361.
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The human interferon (IFN) response is a key innate immune mechanism to fight virus infection. IFNs are host-encoded secreted proteins, which induce IFN-stimulated genes (ISGs) with antiviral properties. Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). In particular, human polymorphisms in IFNL gene loci correlate with hepatitis C disease progression and with treatment response. To date, the underlying mechanisms remain mostly elusive; however it seems clear that viral infection of the liver induces IFNL responses. As IFNL receptors show a more restricted tissue expression than receptors for other classes of IFNs, IFNL treatment has reduced side effects compared to the classical type I IFN treatment. In HCV therapy, however, IFNL will likely not play an important role as highly effective direct acting antivirals (DAA) exist. Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Finally, we will discuss the lessons learnt from the HCV and IFNL field for virus infections beyond hepatitis C.
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Khan, O. A., H. Jiang, P. S. Subramaniam, H. M. Johnson, and S. S. Dhib-Jalbut. "Immunomodulating functions of recombinant ovine interferon tau: potential for therapy in mulitple sclerosis and autoimmune disorders." Multiple Sclerosis Journal 4, no. 2 (April 1998): 63–69. http://dx.doi.org/10.1177/135245859800400204.
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The interferons (IFN) are a family of complex proteins possessing antiviral, antiproliferative, and immunomodulatory activities. Two type 1 recombinant human IFN have been recently approved for the treatment of multiple sclerosis (MS). However, use of high dose type 1 IFN treatment in MS patients has been limited by dose-related toxicity. Ovine IFNt is a unique type 1 interferon discovered for its role in the animal reproductive cycle. It differs from other type 1 IFNs in that it is remarkably less toxic even at high concentrations, is able to cross species barriers, and is not inducible by viral infection. Ovine IFNt has been shown to be very effective in the treatment of animal models of MS. In this study, we examined the toxicity of OvIFNt on human T-cells at high doses and its immunregulatory properties at equivalent doses. Our experiments confirmed the remarkably non-toxic nature of OvIFNt on human cells at high concentrations as well as immunomodulating properties consistent with other type 1 IFNs including an antilymphoproliferative effect and inhibition of IFNg-induced HLA class II expression. These results suggest that OvIFNt could be developed into a potentially less toxic therapeutic option for immune-mediated disorders including MS.
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Bauersachs, S., S. E. Ulbrich, H. D. Reichenbach, M. Reichenbach, M. Büttner, H. H. D. Meyer, T. E. Spencer, et al. "83 EFFECTS OF HUMAN INTERFERON-α ON GENE EXPRESSION IN THE BOVINE ENDOMETRIUM IN COMPARISON TO DAYS 15 AND 18 OF PREGNANCY." Reproduction, Fertility and Development 24, no. 1 (2012): 154. http://dx.doi.org/10.1071/rdv24n1ab83.
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Interferon-τ (IFNT), a Type-I interferon (IFN), is the pregnancy recognition signal produced by the ruminant conceptus (Godkin et al. 1984; Hansen et al. 1985; Helmer et al. 1987; Spencer et al. 2007). In addition to these specific functions of IFNT in ruminants, many studies suggest that IFNs play a general role in establishment of pregnancy and conceptus attachment/implantation in most mammalian species (Bazer et al. 2009; Bazer et al. 2010; Johnson et al. 2009; Roberts et al. 2008). To characterise the effects of prototype Type-I IFNs on bovine endometrium, in experiment one, Simmental heifers were treated from Day 14 to Day 16 of the oestrous cycle with a rod-shaped intrauterine device releasing human interferon-α (IFNA) or placebo lipid extrudates or PBS only as controls (n = 4 each). Lipid formulation and concentration of human IFNA were adjusted to release 8–9 × 107 IU of IFNA over a period of 2 days in in vitro release experiments. On Day 16, endometrial biopsy samples were collected after flushing the uterus. In experiment 2, endometrial tissue samples were obtained on Day 12, 15 and 18 post-mating from nonpregnant or pregnant heifers. All samples from both experiments were analysed with an Affymetrix Bovine Genome Array (Santa Clara, CA). In experiment one, IFNA treatment resulted in differential gene expression in the bovine endometrium. Significant differences were found between the IFNA group and both control groups, whereas no differences were observed between the placebo and the PBS control group. In experiment 2, differentially expressed genes were found between pregnant and nonpregnant endometria on Day 15 and 18, but not on Day 12, with many of them known IFN-stimulated genes. The comparison of the data sets from both experiments showed very similar gene expression changes for most of the typical IFN-stimulated genes. In addition, several genes were identified which were differentially expressed after IFNA treatment but not different at Day 15 or 18 of pregnancy compared with nonpregnant animals. Conversely, some genes were found as differentially expressed during pregnancy but not after IFNA treatment. Differential expression of selected genes was verified by quantitative real-time PCR and 4 genes, namely jumonji C domain containing histone demethylase 1 homologue D (JHDM1D), indoleamine 2,3-dioxygenase 1 (IDO1), fatty acid binding protein 3, muscle and heart (mammary-derived growth inhibitor) (FABP3) and dickkopf homologue 1 (DKK1), were selected for localization of mRNA expression in endometrial tissue sections. The findings of this study suggest that there may be differential effects of bovine IFNT compared with human IFNA and that some pregnancy-specific changes in the endometrium are elicited by conceptus-derived factors other than IFNT. This study was supported by the German Ministry for Education and Research (BMBF, FUGATO-plus, COMPENDIUM) and the German Research Foundation (DFG FOR478). The authors are part of the European Union COST action GEMINI.
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Shank, Kaitlyn, Yusup Shin, Carson Wills, Nicole Cunningham, Alevtina Domashenko, Russell Garrett, Jenni A. Punt, and Stephen G. Emerson. "IFNs Upregulate Sca-1 and Block Proliferation in Murine Hematopoietic Stem and Progenitor Cells,." Blood 118, no. 21 (November 18, 2011): 3394. http://dx.doi.org/10.1182/blood.v118.21.3394.3394.
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Abstract Abstract 3394 Hematopoietic stem cells (HSC) replenish the cellular components of the blood throughout life by a homeostatic process in which the majority of HSCs remain quiescent while a small percentage enter the cell cycle to either self-review or differentiate. During inflammatory responses to infections, Interferons (IFNa, IFNg) perturb HSC homeostasis, presumably in response to the demand for increased numbers of inflammatory cells. Previous studies have highlighted an apparent paradox, i.e. IFNs suppress the proliferation of normally cycling murine hematopoietic progenitor cells (HPCs), yet increase the fraction of normally quiescent Sca+ HSCs that proliferate. To investigate the mechanisms underlying this paradox, we dissected the dynamics of cell surface phenotypes, cell cycle kinetics, pro- and anti-apoptotic pathways within the HSC and HPC compartments in response to pIpC and IFNs both in vivo and in vitro. Forty-eight hours after pIpC injection, bone marrow (BM) cellularity declined by 60%, the proportion of Sca- kit+ HPCs fell from 0.45% to 0.05%, while the proportion of BM cells with the Sca+ kit+ HSC phenotype increased from 0.17 to 0.26%. To determine whether the increase in Sca+kit+ cells was due to proliferation of HSCs or upregulation of Sca-1 on HPCs, we cultured purified CD150+ Sca-Kit+ HPCs and CD150+Sca+kit+ HSCs in vitro with IFNa, IFNg, or PBS. Sca expression was induced on previously Sca- HPCs, and the level of Sca expression on HSCs was also increased. This induction was detectable as early as 6 hours after treatment and accompanied by an increase in Sca mRNA. BrdU incorporation into both HPC and HSC populations decreased from pre-treatment baselines, further indicating that the increase in cells with the HSC phenotype was not due to HSC proliferation, but rather the appearance of cycling HPCs within the HSC staining gate following IFN-induced upregulation of Sca. Staining with FITC-DEVD-FMK identified active cleaved capase-3 in pIpC- or IFN-treated cells, suggesting that the reduced cellularity following IFN reflected a cellular stress that killed Lin+ precursors cells and some HPCs, but spared HSCs. In contrast to lin+kit- precursors, all kit + HPCs and HSCs expressed bcl-2, suggesting that expression of anti-apoptotic proteins may prevent IFN-induced stress from resulting in HSC/HPC apoptosis despite the initial triggering of caspase-3 cleavage. In summary, acute treatment with IFNs has anti-proliferative effects on all hematopoietic cells, including precursors, HPCs and HSCs, with the apparent increase in HSC proliferation the result of HPCs masquerading as Sca+HSCs after exposure to IFN. Unlike precursors, HSCs and some HPCs survive treatment to IFNs despite activation of cleaved caspase-3, possibly due to their expression of bcl-2, and likely related anti-apoptotic regulators. The previously observed increase in HSC proliferation days and weeks following IFN treatment is most likely due to the homeostatic response of HSCs to the depopulation of the precursor and HPCs caused by acute IFN exposure. Disclosures: No relevant conflicts of interest to declare.
5
Leavy, Olive. "IFNs boost cancer killers." Nature Reviews Immunology 11, no. 11 (October 25, 2011): 719. http://dx.doi.org/10.1038/nri3094.
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Snyder, Deann T., Jodi F. Hedges, and Mark A. Jutila. "Getting “Inside” Type I IFNs: Type I IFNs in Intracellular Bacterial Infections." Journal of Immunology Research 2017 (2017): 1–17. http://dx.doi.org/10.1155/2017/9361802.
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Type I interferons represent a unique and complex group of cytokines, serving many purposes during innate and adaptive immunity. Discovered in the context of viral infections, type I IFNs are now known to have myriad effects in infectious and autoimmune disease settings. Type I IFN signaling during bacterial infections is dependent on many factors including whether the infecting bacterium is intracellular or extracellular, as different signaling pathways are activated. As such, the repercussions of type I IFN induction can positively or negatively impact the disease outcome. This review focuses on type I IFN induction and downstream consequences during infection with the following intracellular bacteria:Chlamydia trachomatis,Listeria monocytogenes,Mycobacterium tuberculosis,Salmonella entericaserovar Typhimurium,Francisella tularensis,Brucella abortus,Legionella pneumophila, andCoxiella burnetii. Intracellular bacterial infections are unique because the bacteria must avoid, circumvent, and even co-opt microbial “sensing” mechanisms in order to reside and replicate within a host cell. Furthermore, life inside a host cell makes intracellular bacteria more difficult to target with antibiotics. Because type I IFNs are important immune effectors, modulating this pathway may improve disease outcomes. But first, it is critical to understand the context-dependent effects of the type I IFN pathway in intracellular bacterial infections.
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Kimura, M., J. A. Majde, L. A. Toth, M. R. Opp, and J. M. Krueger. "Somnogenic effects of rabbit and recombinant human interferons in rabbits." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 267, no. 1 (July 1, 1994): R53—R61. http://dx.doi.org/10.1152/ajpregu.1994.267.1.r53.
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Interferons (IFNs) are antiviral cytokines that possess several central nervous system activities. IFN therapy is associated with sleepiness, and the IFNs expressed during viral infection may be involved in the excess sleep associated with these infections. Most viruses stimulate the production of both IFN-alpha and IFN-beta. Although large doses of human IFN-alpha 2 are somnogenic in rabbits, the effects of species-specific IFNs on sleep in the rabbit have not been documented. We compared the somnogenic and antiviral effects of IFNs derived from rabbits to the effects of recombinant human (rh) IFN-alpha and IFN-beta. When injected intracerebroventricularly, rhIFN-alpha A/D, rabbit IFN-alpha/beta, and rabbit reference IFN induced non-rapid-eye-movement sleep and fever in a dose-dependent manner. However, the doses of rabbit IFNs required to induce sleep were much lower than those of human IFNs. Heat treatment of both rabbit IFNs and human IFNs greatly reduced their in vitro antiviral effects. The in vivo activities of rabbit IFNs and rhIFN-alpha A/D were significantly attenuated after heat treatment. However, rhIFN-beta retained its sleep-promoting action after heat treatment, suggesting that microbial contaminants were responsible for its somnogenic and pyrogenic activities. We conclude that IFN-alpha is somnogenic.
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Chandrasekaran, Sanjay, Maiko Sasaki, and Brian Paul Pollack. "PTEN/PI3K signaling in cancer and the response to cytokines: From growth factors to immune actors." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 35. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.35.
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35 Background: The PTEN/PIK3 pathway plays an important role in the cellular response to growth factors and aberrant activation of PI3K signaling is a hallmark of many forms of cancer. While the role of PI3K signaling has been well studied in the context of growth factor biology, its role in the cellular response to cytokines such as interferons (IFNs) is less well understood. We examined the impact of PI3K activation on interferon signaling pathways using an in vitro experimental model system. Methods: Cultured human HCT 116 colorectal carcinoma cells and isogenic PTEN (-/-) cells were treated with escalating doses of IFNg, IFNa2b, and IFNl. IFN response was evaluated by measuring MHC Class I and Class II mRNA levels and cell surface expression via RT-PCR and flow cytometry, respectively. Western blots for total AKT, phospho-AKT (pAKT), PTEN, STAT1, and pSTAT1 were performed. Corroborating pharmacologic studies were performed using cultured HPV-negative SqCC/Y1 oSCC cells treated with IFN and the PTEN inhibitor VO-OHpic and AKT activator SC79. Clinical correlates utilizing immunohistochemistry (IHC) on human head and neck cancers were conducted. Results: PTEN (-/-) cells expressed lower basal levels of MHC I and the induction by IFNs were likewise attenuated. Dramatically, PTEN knockout reduced IFN-g- induced surface expression of MHC II by > 50%. Corresponding reductions in MHC I/II mRNA were seen. IHC in patient biopsy samples showed an inverse relationship between phospho-AKT and MHC I expression. We identified a potential explanation of this effect wherein PTEN/PIK3 signaling implicates STAT1, a downstream target of IFN signaling. PTEN inhibition consistently modulated total and phosphorylated levels of STAT1 protein. Conclusions: Much remains unknown about the link between growth factor pathways and the tumor immune response. We demonstrate using an in vitro model that genetic and pharmacologic activation of the PI3K pathway attenuates the immune response to IFNs and represses MHC induction and expression. We present a novel mechanism for explaining this phenomenon linking the PTEN/PIK3 and STAT1 pathways. Further characterization of this interaction in in vitro models is necessary.
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Abdolvahab, Mohadeseh Haji, Behrad Darvishi, Mohammad Zarei, Keivan Majidzadeh-A, and Leila Farahmand. "Interferons: role in cancer therapy." Immunotherapy 12, no. 11 (August 2020): 833–55. http://dx.doi.org/10.2217/imt-2019-0217.
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Interferons (IFNs) are a group of signaling cytokines, secreted by host cells to induce protection against various disorders. IFNs can directly impact on tumor cells or indirectly induce the immune system to protect host cells. The expression levels of IFNs and its functions of are excellently modulated in a way to protect host cells from probable toxicities caused by extreme responses. The efficacy of anticancer therapies is correlated to IFNs signaling. Although IFN signaling is involved in induction of antitumor responses, chronic stimulation of the IFN signaling pathway can induce resistance to various antineoplasm therapies. Hence, IFNs are expressed by both cancer and immune cells, and modulate their biological function. Understanding this mechanism of action might be a key target of combination therapies.
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Chen, Yongzhi, Xuqiu Lei, Zhaozhao Jiang, and Katherine A. Fitzgerald. "Cellular nucleic acid–binding protein is essential for type I interferon–mediated immunity to RNA virus infection." Proceedings of the National Academy of Sciences 118, no. 26 (June 24, 2021): e2100383118. http://dx.doi.org/10.1073/pnas.2100383118.
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Type I interferons (IFNs) are innate immune cytokines required to establish cellular host defense. Precise control of IFN gene expression is crucial to maintaining immune homeostasis. Here, we demonstrated that cellular nucleic acid–binding protein (CNBP) was required for the production of type I IFNs in response to RNA virus infection. CNBP deficiency markedly impaired IFN production in macrophages and dendritic cells that were infected with a panel of RNA viruses or stimulated with synthetic double-stranded RNA. Furthermore, CNBP-deficient mice were more susceptible to influenza virus infection than were wild-type mice. Mechanistically, CNBP was phosphorylated and translocated to the nucleus, where it directly binds to the promoter of IFNb in response to RNA virus infection. Furthermore, CNBP controlled the recruitment of IFN regulatory factor (IRF) 3 and IRF7 to IFN promoters for the maximal induction of IFNb gene expression. These studies reveal a previously unrecognized role for CNBP as a transcriptional regulator of type I IFN genes engaged downstream of RNA virus–mediated innate immune signaling, which provides an additional layer of control for IRF3- and IRF7-dependent type I IFN gene expression and the antiviral innate immune response.
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Wang, Shuai, Shan Nan Chen, Zheng Sun, An Ning Pang, Su Wang, Lan Hao Liu, Yang Liu, and P. Nie. "Four type I IFNs, IFNa1, IFNa2, IFNb, IFNc, and their receptor usage in an osteoglossomorph fish, the Asian arowana, Scleropages formosus." Fish & Shellfish Immunology 117 (October 2021): 70–81. http://dx.doi.org/10.1016/j.fsi.2021.07.012.
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Ealy, Alan D., and Lydia K. Wooldridge. "The evolution of interferon-tau." Reproduction 154, no. 5 (November 2017): F1—F10. http://dx.doi.org/10.1530/rep-17-0292.
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Thirty years ago, a novel type I interferon (IFN) was identified by molecular cloning of cDNA libraries constructed from RNA extracted from ovine and bovine pre-implantation embryos. This protein was eventually designated as IFN-tau (IFNT) to highlight its trophoblast-dependent expression. IFNT function is not immune related. Instead, it interacts with the maternal system to initiate the establishment and maintenance of pregnancy. This activity is indispensable for the continuation of pregnancy. Our review will describe how IFNT evolved from other type I IFNs to function in this new capacity. IFNT genes have only been identified in pecoran ruminants within the Artiodactyla order (e.g. cattle, sheep, goats, deer, antelope, giraffe). The ancestral IFNT gene emerged approximately 36 million years ago most likely from rearrangement and/or insertion events that combined an ancestral IFN-omega (IFNW) gene with a trophoblast-specifying promoter/enhancer. Since then, IFNT genes have duplicated, likely through conversion events, and mutations have allowed them to adapt to their new function in concert with the emergence of different species. Multiple IFNT polymorphisms have been identified in cattle, sheep and goats. These genes and gene alleles encode proteins that do not display identical antiviral, antiproliferative and antiluteolytic activities. The need for multiple IFNT genes, numerous alleles and distinct activities remains debatable, but the consensus is that this complexity in IFNT expression and biological activity must be needed to provide the best opportunity for pregnancy to be recognized by the maternal system so that gestation may continue.
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Stanifer, Megan L., Kalliopi Pervolaraki, and Steeve Boulant. "Differential Regulation of Type I and Type III Interferon Signaling." International Journal of Molecular Sciences 20, no. 6 (March 21, 2019): 1445. http://dx.doi.org/10.3390/ijms20061445.
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Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.
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Tagawa, Masatoshi, Kiyoko Kawamura, Quanhai Li, Yuji Tada, Kenzo Hiroshima, and Hideaki Shimada. "A Possible Anticancer Agent, Type III Interferon, Activates Cell Death Pathways and Produces Antitumor Effects." Clinical and Developmental Immunology 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/479013.
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Recently identified interleukin-28 and -29 belong to a novel type III interferon (IFN) family, which could have distinct biological properties from type I and II IFNs. Type I IFNs, IFN-α/β, have been clinically applied for treating a certain kind of malignancies for over 30 years, but a wide range of the adverse effects hampered the further clinical applications. Type III IFNs, IFN-λs, have similar signaling pathways as IFN-α/βand inhibits proliferation of tumor cells through cell cycle arrest or apoptosis. Restricted patterns of type III IFN receptor expression in contrast to ubiquitously expressed IFN-α/βreceptors suggest that type III IFNs have limited cytotoxicity to normal cells and can be a possible anticancer agent. In this paper, we summarize the current knowledge on the IFN-λs-mediated tumor cell death and discuss the functional difference between type I and III IFNs.
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Fenton, Sarah E., Diana Saleiro, and Leonidas C. Platanias. "Type I and II Interferons in the Anti-Tumor Immune Response." Cancers 13, no. 5 (March 2, 2021): 1037. http://dx.doi.org/10.3390/cancers13051037.
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The interferons (IFNs) are essential components of the immune response against infections and malignancies. IFNs are potent promoters of the anti-tumor response, but there is also evidence that feedback mechanisms regulated by IFNs negatively control immune responses to avoid hyper-activation and limit inflammation. This balance of responses plays an important role in cancer surveillance, immunoediting and response to anticancer therapeutic approaches. Here we review the roles of both type I and type II IFNs on the control of the immune response against malignancies in the context of effects on both malignant cells and cells of the immune system in the tumor microenvironment.
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Bertzbach, Luca D., Olof Harlin, Sonja Härtle, Frank Fehler, Tereza Vychodil, Benedikt B. Kaufer, and Bernd Kaspers. "IFNα and IFNγ Impede Marek’s Disease Progression." Viruses 11, no. 12 (November 28, 2019): 1103. http://dx.doi.org/10.3390/v11121103.
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Marek’s disease virus (MDV) is an alphaherpesvirus that causes Marek’s disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect animals from clinical disease, they do not provide sterilizing immunity and allow field strains to circulate and evolve in vaccinated flocks. Therefore, there is a need for improved vaccines and for a better understanding of innate and adaptive immune responses against MDV infections. Interferons (IFNs) play important roles in the innate immune defenses against viruses and induce upregulation of a cellular antiviral state. In this report, we quantified the potent antiviral effect of IFNα and IFNγ against MDV infections in vitro. Moreover, we demonstrate that both cytokines can delay Marek’s disease onset and progression in vivo. Additionally, blocking of endogenous IFNα using a specific monoclonal antibody, in turn, accelerated disease. In summary, our data reveal the effects of IFNα and IFNγ on MDV infection and improve our understanding of innate immune responses against this oncogenic virus.
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Li, Yuanyuan, Yueqi Song, Leqing Zhu, Xiao Wang, Brittany Richers, Donald Y. M. Leung, and Lianghua Bin. "Interferon Kappa Is Important for Keratinocyte Host Defense against Herpes Simplex Virus-1." Journal of Immunology Research 2020 (January 3, 2020): 1–8. http://dx.doi.org/10.1155/2020/5084682.
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Type I interferon kappa (IFNκ) is selectively expressed in human keratinocytes. Herpes simplex virus-1 (HSV-1) is a human pathogen that infects keratinocytes and causes lytic skin lesions. Whether IFNκ plays a role in keratinocyte host defense against HSV-1 has not been investigated. In this study, we found that IFNκ mRNA expression was induced by addition of recombinant IFNκ and poly (I:C); and its expression level was significantly greater than IFNa2, IFNb1, and IFNL1 in both undifferentiated and differentiated normal human epidermal keratinocytes (NHEKs) under resting and stimulation conditions. Although IFNe was expressed at a relatively higher level than other IFNs in resting undifferentiated NHEK, its expression level did not change after stimulation with recombinant IFNκ and poly (I:C). HSV-1 infection inhibited gene expression of IFNκ and IFNe in NHEK. Silencing IFNκ in NHEK led to significantly enhanced HSV-1 replication in both undifferentiated and differentiated NHEK compared to scrambled siRNA-transfected cells, while the addition of recombinant IFNκ significantly reduced HSV-1 replication in NHEK. In addition, we found that IFNκ did not regulate protein expression of NHEK differentiation markers. Our results demonstrate that IFNκ is the dominant type of IFNs in keratinocytes and it has an important function for keratinocytes to combat HSV-1 infection.
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Oliveira, Danilo Bretas de, Gabriel Magno de Freitas Almeida, Antônio Carlos Martins Guedes, Flávia Patrícia Sena Teixeira Santos, Claudio Antônio Bonjardim, Paulo César Peregrino Ferreira, and Erna Geessien Kroon. "Basal Activation of Type I Interferons (Alpha2 and Beta) and2′5′OAS Genes: Insights into Differential Expression Profiles of Interferon System Components in Systemic Sclerosis." International Journal of Rheumatology 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/275617.
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Objective. Systemic sclerosis (SSc) is a complex autoimmune disease in which interferons (IFNs) may play an essential role. We hypothesized that type I and III IFNs may be found in increased levels in patients and be responsible for SSc autoimmune status.Methods. Type I and III IFN and ISG basal expression profiles were measured by qPCR using RNA from PBMCs of patients and controls .Results. Type I IFNs are increased in SSc patients, while no induction of type III IFNs was detected. This induction cannot be related to IRF7, since no upregulation of this gene was seen on patients. Of the ISGs tested, 2′5′OAS levels were increased in patients, while 6–16 and MxA levels were not.Conclusions. While there is no indication of type III IFN induction, increased levels of type I IFNs may lead to abnormal regulation of ISGs that can be responsible for immune system alterations described for SSc.
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Sharif, M. Nusrat, Dražen Šošić, Carla V. Rothlin, Erin Kelly, Greg Lemke, Eric N. Olson, and Lionel B. Ivashkiv. "Twist mediates suppression of inflammation by type I IFNs and Axl." Journal of Experimental Medicine 203, no. 8 (July 10, 2006): 1891–901. http://dx.doi.org/10.1084/jem.20051725.
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Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFα production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFα production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFα production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-κB–dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFα production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.
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Yavuz, Enes. "Tauberian theorems for statistical Cesàro and statistical logarithmic summability of sequences in intuitionistic fuzzy normed spaces." Journal of Intelligent & Fuzzy Systems 40, no. 6 (June 21, 2021): 12433–42. http://dx.doi.org/10.3233/jifs-210596.
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We define statistical Cesàro and statistical logarithmic summability methods of sequences in intuitionistic fuzzy normed spaces(IFNS) and give slowly oscillating type and Hardy type Tauberian conditions under which statistical Cesàro summability and statistical logarithmic summability imply convergence in IFNS. Besides, we obtain analogous results for the higher order summability methods as corollaries. Also, two theorems concerning the convergence of statistically convergent sequences in IFNS are proved in the paper.
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Manry, Jérémy, Guillaume Laval, Etienne Patin, Simona Fornarino, Yuval Itan, Matteo Fumagalli, Manuela Sironi, et al. "Evolutionary genetic dissection of human interferons." Journal of Experimental Medicine 208, no. 13 (December 12, 2011): 2747–59. http://dx.doi.org/10.1084/jem.20111680.
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Interferons (IFNs) are cytokines that play a key role in innate and adaptive immune responses. Despite the large number of immunological studies of these molecules, the relative contributions of the numerous IFNs to human survival remain largely unknown. Here, we evaluated the extent to which natural selection has targeted the human IFNs and their receptors, to provide insight into the mechanisms that govern host defense in the natural setting. We found that some IFN-α subtypes, such as IFN-α6, IFN-α8, IFN-α13, and IFN-α14, as well as the type II IFN-γ, have evolved under strong purifying selection, attesting to their essential and nonredundant function in immunity to infection. Conversely, selective constraints have been relaxed for other type I IFNs, particularly for IFN-α10 and IFN-ε, which have accumulated missense or nonsense mutations at high frequencies within the population, suggesting redundancy in host defense. Finally, type III IFNs display geographically restricted signatures of positive selection in European and Asian populations, indicating that genetic variation at these genes has conferred a selective advantage to the host, most likely by increasing resistance to viral infection. Our population genetic analyses show that IFNs differ widely in their biological relevance, and highlight evolutionarily important determinants of host immune responsiveness.
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Kayagaki, Nobuhiko, Noriko Yamaguchi, Masafumi Nakayama, Hiroshi Eto, Ko Okumura, and Hideo Yagita. "Type I Interferons (IFNs) Regulate Tumor Necrosis Factor–related Apoptosis-inducing Ligand (TRAIL) Expression on Human T Cells: A Novel Mechanism for the Antitumor Effects of Type I IFNs." Journal of Experimental Medicine 189, no. 9 (May 3, 1999): 1451–60. http://dx.doi.org/10.1084/jem.189.9.1451.
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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a proapoptotic member of the TNF family of type II membrane proteins, which constitutes one component of T cell cytotoxicity. In this study, we investigated the expression and function of TRAIL in human peripheral blood T (PBT) cells. Although freshly isolated PBT cells did not express a detectable level of TRAIL on their surface, a remarkable TRAIL expression was rapidly induced on the surface of both CD4+ and CD8+ PBT cells upon stimulation with anti-CD3 monoclonal antibody and type I interferons (IFNs). This enhancement of TRAIL expression was a unique feature of type I IFNs (IFN-α and IFN-β), and neither type II IFN (IFN-γ) nor various other cytokines enhanced TRAIL expression on anti-CD3–stimulated PBT cells. Type I IFNs have been used for clinical treatment of renal cell carcinomas (RCCs), and we found that most RCC cell lines were susceptible to TRAIL-induced apoptosis. Type I IFNs substantially augmented cytotoxic activity of anti-CD3–stimulated PBT cells against RCC cell lines in a TRAIL-dependent manner. These results indicate a unique feature of type I IFNs to regulate TRAIL-mediated T cell cytotoxicity, which may be involved in the antitumor effects of type I IFNs against various tumors.
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Lousberg, Erin L., Cara K. Fraser, Michael G. Tovey, Kerrilyn R. Diener, and John D. Hayball. "Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity." Journal of Virology 84, no. 13 (April 21, 2010): 6549–63. http://dx.doi.org/10.1128/jvi.02618-09.
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ABSTRACT Type I interferons (IFNs) are considered to be important mediators of innate immunity due to their inherent antiviral activity, ability to drive the transcription of a number of genes involved in viral clearance, and their role in the initiation of innate and adaptive immune responses. Due to the central role of type I IFNs, we sought to determine their importance in the generation of immunity to a recombinant vaccine vector fowlpox virus (FPV). In analyzing the role of type I IFNs in immunity to FPV, we show that they are critical to the secretion of a number of innate and proinflammatory cytokines, including type I IFNs themselves as well as interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β, and that deficiency leads to enhanced virus-mediated antigen expression. Interestingly, however, type I IFNs were not required for adaptive immune responses to recombinant FPV even though plasmacytoid dendritic cells (pDCs), the primary producers of type I IFNs, have been shown to be requisite for this to occur. Furthermore, we provide evidence that the importance of pDCs may lie in their ability to capture and present virally derived antigen to T cells rather than in their capacity as professional type I IFN-producing cells.
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Zimmermann, Albert, Mirko Trilling, Markus Wagner, Manuel Wilborn, Ivan Bubic, Stipan Jonjic, Ulrich Koszinowski, and Hartmut Hengel. "A cytomegaloviral protein reveals a dual role for STAT2 in IFN-γ signaling and antiviral responses." Journal of Experimental Medicine 201, no. 10 (May 9, 2005): 1543–53. http://dx.doi.org/10.1084/jem.20041401.
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A mouse cytomegalovirus (MCMV) gene conferring interferon (IFN) resistance was identified. This gene, M27, encodes a 79-kD protein that selectively binds and down-regulates for signal transducer and activator of transcription (STAT)-2, but it has no effect on STAT1 activation and signaling. The absence of pM27 conferred MCMV susceptibility to type I IFNs (α/β), but it had a much more dramatic effect on type II IFNs (γ) in vitro and in vivo. A comparative analysis of M27+ and M27− MCMV revealed that the antiviral efficiency of IFN-γ was partially dependent on the synergistic action of type I IFNs that required STAT2. Moreover, STAT2 was directly activated by IFN-γ. This effect required IFN receptor expression and was independent of type I IFNs. IFN-γ induced increasing levels of tyrosine-phosphorylated STAT2 in M27− MCMV-infected cells that were essential for the antiviral potency of IFN-γ. pM27 represents a new strategy for simultaneous evasions from types I and II IFNs, and it documents an unknown biological significance for STAT2 in antiviral IFN-γ responses.
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Wu, Wenxin, and Jordan P. Metcalf. "The Role of Type I IFNs in Influenza: Antiviral Superheroes or Immunopathogenic Villains?" Journal of Innate Immunity 12, no. 6 (2020): 437–47. http://dx.doi.org/10.1159/000508379.
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The important role of interferons (IFNs) in antiviral innate immune defense is well established. Although recombinant IFN-α was approved for cancer and chronic viral infection treatment by regulatory agencies in many countries starting in 1986, no IFNs are approved for treatment of influenza A virus (IAV) infection. This is partially due to the complex effects of IFNs in acute influenza infection. IAV attacks the human respiratory system and causes significant morbidity and mortality globally. During influenza infection, depending on the strain of IAV and the individual host, type I IFNs can have protective antiviral effects or can contribute to immunopathology. In the context of virus infection, the immune system has complicated mechanisms regulating the expression and effects of type I IFN to maximize the antiviral response by both activating and enhancing beneficial innate cell function, while limiting immunopathological responses that lead to exaggerated tissue damage. In this review, we summarize the complicated, but important, role of type I IFNs in influenza infections. This includes both protective and harmful effects of these important cytokines during infection.
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Melchjorsen, Jesper, Johanna Rintahaka, Stine Søby, Kristy A. Horan, Alina Poltajainen, Lars Østergaard, Søren R. Paludan, and Sampsa Matikainen. "Early Innate Recognition of Herpes Simplex Virus in Human Primary Macrophages Is Mediated via the MDA5/MAVS-Dependent and MDA5/MAVS/RNA Polymerase III-Independent Pathways." Journal of Virology 84, no. 21 (August 25, 2010): 11350–58. http://dx.doi.org/10.1128/jvi.01106-10.
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ABSTRACT Innate recognition of viruses is mediated by pattern recognition receptors (PRRs) triggering expression of antiviral interferons (IFNs) and proinflammatory cytokines. In mice, Toll-like receptor 2 (TLR2) and TLR9 as well as intracellular nucleotide-sensing pathways have been shown to recognize herpes simplex virus (HSV). Here, we describe how human primary macrophages recognize early HSV infection via intracellular pathways. A number of inflammatory cytokines, IFNs, and IFN-stimulated genes were upregulated after HSV infection. We show that early recognition of HSV and induction of IFNs and inflammatory cytokines are independent of TLR2 and TLR9, since inhibition of TLR2 using TLR2 neutralizing antibodies did not affect virus-induced responses and the macrophages were unresponsive to TLR9 stimulation. Instead, HSV recognition involves intracellular recognition systems, since induction of tumor necrosis factor alpha (TNF-α) and IFNs was dependent on virus entry and replication. Importantly, expression of IFNs was strongly inhibited by small interfering RNA (siRNA) knockdown of MAVS, but this MAVS-dependent IFN induction occurred independently of the recently discovered polymerase III (Pol III)/RIG-I DNA sensing system. In contrast, induction of TNF-α was largely independent of MAVS, suggesting that induction of inflammatory cytokines during HSV infection proceeds via a novel pathway. Transfection with ODN2006, a broad inhibitor of intracellular nucleotide recognition, revealed that nucleotide-sensing systems are employed to induce both IFNs and TNF-α. Finally, using siRNA knockdown, we found that MDA5, but not RIG-I, was the primary mediator of HSV recognition. Thus, innate recognition of HSV by human primary macrophages occurs via two distinct intracellular nucleotide-sensing pathways responsible for induction of IFNs and inflammatory cytokine expression, respectively.
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Leib, David A., Travis E. Harrison, Kathleen M. Laslo, Michael A. Machalek, Nathaniel J. Moorman, and Herbert W. Virgin. "Interferons Regulate the Phenotype of Wild-type and Mutant Herpes Simplex Viruses In Vivo." Journal of Experimental Medicine 189, no. 4 (February 15, 1999): 663–72. http://dx.doi.org/10.1084/jem.189.4.663.
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Mechanisms responsible for neuroattenuation of herpes simplex virus (HSV) have been defined previously by studies of mutant viruses in cultured cells. The hypothesis that null mutations in host genes can override the attenuated phenotype of null mutations in certain viral genes was tested. Mutants such as those in infected cell protein (ICP) 0, thymidine kinase, ribonucleotide reductase, virion host shutoff, and ICP34.5 are reduced in their capacity to replicate in nondividing cells in culture and in vivo. The replication of these viruses was examined in eyes and trigeminal ganglia for 1–7 d after corneal inoculation in mice with null mutations (−/−) in interferon receptors (IFNR) for type I IFNs (IFN-α/βR), type II IFN (IFN-γR), and both type I and type II IFNs (IFN-α/β/γR). Viral titers in eyes and ganglia of IFN-γR−/− mice were not significantly different from congenic controls. However, in IFN-α/βR−/− or IFN-α/β/γR−/− mice, growth of all mutants, including those with significantly impaired growth in cell culture, was enhanced by up to 1,000-fold in eyes and trigeminal ganglia. Blepharitis and clinical signs of infection were evident in IFN-α/βR−/− and IFN-α/β/γR−/− but not control mice for all viruses. Also, IFNs were shown to significantly reduce productive infection of, and spread from intact, but not scarified, corneas. Particularly striking was restoration of near-normal trigeminal ganglion replication and neurovirulence of an ICP34.5 mutant in IFN-α/βR−/− mice. These data show that IFNs play a major role in limiting mutant and wild-type HSV replication in the cornea and in the nervous system. In addition, the in vivo target of ICP34.5 may be host IFN responses. These experiments demonstrate an unsuspected role for host factors in defining the phenotypes of some HSV mutants in vivo. The phenotypes of mutant viruses therefore cannot be interpreted based solely upon studies in cell culture but must be considered carefully in the context of host factors that may define the in vivo phenotype.
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Sang, Yongming, Raymond R. R. Rowland, Richard A. Hesse, and Frank Blecha. "Differential expression and activity of the porcine type I interferon family." Physiological Genomics 42, no. 2 (July 2010): 248–58. http://dx.doi.org/10.1152/physiolgenomics.00198.2009.
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Type I interferons (IFNs) are central to innate and adaptive immunity, and many have unique developmental and physiological functions. However, in most species, only two subtypes, IFN-α and IFN-β, have been well studied. Because of the increasing importance of zoonotic viral diseases and the use of pigs to address human research questions, it is important to know the complete repertoire and activity of porcine type I IFNs. Here we show that porcine type I IFNs comprise at least 39 functional genes distributed along draft genomic sequences of chromosomes 1 and 10. These functional IFN genes are classified into 17 IFN-α subtypes, 11 IFN-δ subtypes, 7 IFN-ω subtypes, and single-subtype subclasses of IFN-αω, IFN-β, IFN-ε, and IFN-κ. We found that porcine type I IFNs have diverse expression profiles and antiviral activities against porcine reproductive and respiratory syndrome virus (PRRSV) and vesicular stomatitis virus (VSV), with activity ranging from 0 to >105 U·ng−1·ml−1. Whereas most IFN-α subtypes retained the greatest antiviral activity against both PRRSV and VSV in porcine and MARC-145 cells, some IFN-δ and IFN-ω subtypes, IFN-β, and IFN-αω differed in their antiviral activity based on target cells and viruses. Several IFNs, including IFN-α7/11, IFN-δ2/7, and IFN-ω4, exhibited minimal or no antiviral activity in the tested target cell-virus systems. Thus comparative studies showed that antiviral activity of porcine type I IFNs is virus- and cell-dependent, and IFN-αs are positively correlated with induction of MxA, an IFN-stimulated gene. Collectively, these data provide fundamental genomic information for porcine type I IFNs, information that is necessary for understanding porcine physiological and antiviral responses.
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Kotenko, Sergei V., Amariliz Rivera, Dane Parker, and Joan E. Durbin. "Type III IFNs: Beyond antiviral protection." Seminars in Immunology 43 (June 2019): 101303. http://dx.doi.org/10.1016/j.smim.2019.101303.
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&NA;. "IFNs may improve efficacy of antineoplastics." Inpharma Weekly &NA;, no. 1401 (August 2003): 8. http://dx.doi.org/10.2165/00128413-200314010-00016.
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Honey, Karen. "pDCs rely on type I IFNs." Nature Reviews Immunology 5, no. 5 (April 20, 2005): 360. http://dx.doi.org/10.1038/nri1618.
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Sgorbissa, Andrea, and Claudio Brancolini. "IFNs, ISGylation and cancer: Cui prodest?" Cytokine & Growth Factor Reviews 23, no. 6 (December 2012): 307–14. http://dx.doi.org/10.1016/j.cytogfr.2012.07.003.
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Ai, Zhenghai, Xiaoqin Shu, and Zeshui Xu. "Foundation of Interval-Valued Intuitionistic Fuzzy Limit and Differential Theory and an Application to Continuous Data." Complexity 2019 (October 27, 2019): 1–14. http://dx.doi.org/10.1155/2019/3947261.
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The intuitionistic fuzzy calculus (IFC), based on the basic operational laws of intuitionistic fuzzy numbers (IFNs), has been put forward. However, the interval-valued IFC (IVIFC), based on the basic operational laws of interval-valued IFNs (IVIFNs), is only in the original stage. To further develop the theory of the IVIFC and make it be rigorous, the primary task is to systematically investigate the characteristics of the limits and differentials, which is a foundation of the IVIFC. Moreover, there is quite a lot of literature on IVIFNs; however, the scholars did not reveal the relationships between IFNs and the IVIFNs. To do that, we first investigate the limit of interval-valued intuitionistic fuzzy sequences, and then, we focus on investigating the limit, the continuity, and the differential of IVIFFs in detail and reveal their relationships. After that, due to the fact that the IFC and the IVIFC are based on the basic operational laws of IFNs and IVIFNs, respectively, we reveal the relationships between the IFNs and the IVIFNs via some homomorphic mappings. Finally, a case study about continuous data of IVIFNs is provided to illustrate the advantages of continuous data.
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Cao, Lili, Guang Yang, Shandian Gao, Chunxia Jing, Ruth R. Montgomery, Yuxin Yin, Penghua Wang, Erol Fikrig, and Fuping You. "HIPK2 is necessary for type I interferon–mediated antiviral immunity." Science Signaling 12, no. 573 (March 19, 2019): eaau4604. http://dx.doi.org/10.1126/scisignal.aau4604.
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Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral responses. In part, HIPK2 interacted with ELF4 and promoted its phosphorylation at Ser369, which enabledIfn-b transcription. In addition, HIPK2 production was stimulated by type I IFNs to further enhance antiviral immunity. These data suggest that the kinase activity and nuclear localization of HIPK2 are essential for the production of type I IFNs.
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Corry, Jacqueline, Nitin Arora, Charles A. Good, Yoel Sadovsky, and Carolyn B. Coyne. "Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal–fetal interface." Proceedings of the National Academy of Sciences 114, no. 35 (August 7, 2017): 9433–38. http://dx.doi.org/10.1073/pnas.1707513114.
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Protecting the fetus from the hematogenous spread of viruses requires multifaceted layers of protection and relies heavily on trophoblasts, the fetal-derived cells that comprise the placental barrier. We showed previously that trophoblasts isolated from full-term placentas resist infection by diverse viruses, including Zika virus (ZIKV), and transfer this resistance to nonplacental cells through the activity of paracrine effectors, including the constitutive release of type III interferons (IFNs). Here, we developed 3D cell-line–based models of human syncytiotrophoblasts, cells that lie in direct contact with maternal blood, and show that these cells recapitulate the antiviral properties of primary trophoblasts through the constitutive release of type III IFNs (IFNλ1 and IFNλ2) and become resistant to ZIKV infection. In addition, using organotypic human midgestation chorionic villous explants, we show that syncytiotrophoblasts isolated from the second trimester of pregnancy also constitutively release type III IFNs and use these IFNs in autocrine and paracrine manners to restrict ZIKV infection. Collectively, these data provide important insights into the defense mechanisms used by syncytiotrophoblasts at various stages of human gestation to resist ZIKV infection and new human models to study the role of type III IFNs in the vertical transmission of ZIKV and other viruses associated with congenital disease.
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Martin, S. A. M., J. B. Taggart, P. Seear, J. E. Bron, R. Talbot, A. J. Teale, G. E. Sweeney, et al. "Interferon type I and type II responses in an Atlantic salmon (Salmo salar) SHK-1 cell line by the salmon TRAITS/SGP microarray." Physiological Genomics 32, no. 1 (December 2007): 33–44. http://dx.doi.org/10.1152/physiolgenomics.00064.2007.
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Interferons (IFNs) are cytokines that have proinflammatory, antiviral, and immunomodulatory effects and play a central role during a host response to pathogens. The IFN family contains both type I and type II molecules. While there are a number of type I IFNs, there is only one type II IFN. Recently both type I and type II IFN genes have been cloned in salmonid fish and recombinant proteins produced showing IFN activity. We have stimulated an Atlantic salmon cell line (SHK-1) with both type I and type II recombinant salmonid IFNs and analyzed the transcriptional response by microarray analysis. Cells were exposed to recombinant IFNs for 6 or 24 h or left unexposed as controls. RNA was hybridized to an Atlantic salmon cDNA microarray (salmon 17K feature TRAITS/SGP array) in order to assess differential gene expression in response to IFN exposure. For IFN I and II, 47 and 72 genes were stimulated, respectively; most genes were stimulated by a single IFN type, but some were affected by both IFNs, indicating coregulation of the IFN response in fish. Real-time PCR analysis was employed to confirm the microarray results for selected differentially expressed genes in both a cell line and primary leukocyte cultures.
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Kotenko, Sergei V., and Joan E. Durbin. "Contribution of type III interferons to antiviral immunity: location, location, location." Journal of Biological Chemistry 292, no. 18 (March 13, 2017): 7295–303. http://dx.doi.org/10.1074/jbc.r117.777102.
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Type I interferons (IFN-α/β) and the more recently identified type III IFNs (IFN-λ) function as the first line of defense against virus infection and regulate the development of both innate and adaptive immune responses. Type III IFNs were originally identified as a novel ligand-receptor system acting in parallel with type I IFNs, but subsequent studies have provided increasing evidence for distinct roles for each IFN family. In addition to their compartmentalized antiviral actions, these two systems appear to have multiple levels of cross-regulation and act coordinately to achieve effective antimicrobial protection with minimal collateral damage to the host.
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Frasca, Loredana, and Roberto Lande. "Overlapping, Additive and Counterregulatory Effects of Type II and I Interferons on Myeloid Dendritic Cell Functions." Scientific World JOURNAL 11 (2011): 2071–90. http://dx.doi.org/10.1100/2011/873895.
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Dendritic cells (DCs) are central player in immunity by bridging the innate and adaptive arms of the immune system (IS). Interferons (IFNs) are one of the most important factors that regulate both innate and adaptive immunity too. Thus, the understanding of how type II and I IFNs modulate the immune-regulatory properties of DCs is a central issue in immunology. In this paper, we will address this point in the light of the most recent literature, also highlighting the controversial data reported in the field. According to the wide literature available, type II as well as type I IFNs appear, at the same time, to collaborate, to induce additive effects or overlapping functions, as well as to counterregulate each one's effects on DC biology and, in general, the immune response. The knowledge of these effects has important therapeutic implications in the treatment of infectious/autoimmune diseases and cancer and indicates strategies for using IFNs as vaccine adjuvants and in DC-based immune therapeutic approaches.
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Muhammad Saqlain, Kashaf Naz, Kashf Gaffar, and Muhammad Naveed Jafar. "Fuzzy Logic Controller." Scientific Inquiry and Review 3, no. 3 (September 20, 2019): 16–29. http://dx.doi.org/10.32350/sir.33.02.
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In this research paper, the impact of water pH on detergent was measured by constructing a Fuzzy Logic Controller (FLC) based on Intuitionistic Fuzzy Numbers (IFNs) by incorporating three linguistic inputs and one output as taken by Saeed. M. et al. [1]. The inference process was carried out using MATLAB fuzzy logic toolbox and the results were compared with FLC based on fuzzy numbers. The objective of the study was the comparison of FLC based on intuitionistic and fuzzy numbers. The results showed that FLC based on IFNs is approximately the same but has more precise values. So, IFNs based FLC can be used in the Instinctive Laundry System.
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Colamonici, OR, P. Domanski, LC Platanias, and MO Diaz. "Correlation between interferon (IFN) alpha resistance and deletion of the IFN alpha/beta genes in acute leukemia cell lines suggests selection against the IFN system." Blood 80, no. 3 (August 1, 1992): 744–49. http://dx.doi.org/10.1182/blood.v80.3.744.744.
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Abstract Homozygous and hemizygous deletions of the interferon A (IFNA) and IFNB genes have been frequently observed in acute leukemia cell lines, primary acute leukemia cases, and gliomas. Because IFNs have an antiproliferative effect, selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype. Although the deletion of the IFNA/B genes could interrupt an autocrine loop that controls cell proliferation, cells would still respond to exogenous IFN alpha/beta and, thus, lesions at the receptor or signal transduction level should also be present to render cells resistant to exogenous IFN alpha/beta. To test if selection against the IFN system was operating in acute leukemias, the sensitivity to the antiproliferative effect of IFN alpha 2 was studied in acute leukemia cell lines with and without alterations of the IFNA/B genes. We found that 10 of 11 acute leukemia cell lines with alterations of the IFNA/B genes were resistant to the antiproliferative effect of IFN alpha 2, whereas only two of eight cell lines with normal IFNA/B genes were IFN- resistant. We then examined the possibility that an alteration of the receptor expression could account for the lack of response to IFN alpha 2. No significant alteration in the expression or structure of the IFN alpha receptor was observed. We also studied the downmodulation of the alpha subunit of the IFN alpha receptor upon IFN alpha 2 binding. One cell line with deletion of the IFNA/B genes showed impaired downmodulation of the IFN alpha receptor. The data presented here suggest that selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype.
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Colamonici, OR, P. Domanski, LC Platanias, and MO Diaz. "Correlation between interferon (IFN) alpha resistance and deletion of the IFN alpha/beta genes in acute leukemia cell lines suggests selection against the IFN system." Blood 80, no. 3 (August 1, 1992): 744–49. http://dx.doi.org/10.1182/blood.v80.3.744.bloodjournal803744.
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Homozygous and hemizygous deletions of the interferon A (IFNA) and IFNB genes have been frequently observed in acute leukemia cell lines, primary acute leukemia cases, and gliomas. Because IFNs have an antiproliferative effect, selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype. Although the deletion of the IFNA/B genes could interrupt an autocrine loop that controls cell proliferation, cells would still respond to exogenous IFN alpha/beta and, thus, lesions at the receptor or signal transduction level should also be present to render cells resistant to exogenous IFN alpha/beta. To test if selection against the IFN system was operating in acute leukemias, the sensitivity to the antiproliferative effect of IFN alpha 2 was studied in acute leukemia cell lines with and without alterations of the IFNA/B genes. We found that 10 of 11 acute leukemia cell lines with alterations of the IFNA/B genes were resistant to the antiproliferative effect of IFN alpha 2, whereas only two of eight cell lines with normal IFNA/B genes were IFN- resistant. We then examined the possibility that an alteration of the receptor expression could account for the lack of response to IFN alpha 2. No significant alteration in the expression or structure of the IFN alpha receptor was observed. We also studied the downmodulation of the alpha subunit of the IFN alpha receptor upon IFN alpha 2 binding. One cell line with deletion of the IFNA/B genes showed impaired downmodulation of the IFN alpha receptor. The data presented here suggest that selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype.
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Chyuan, I.-Tsu, Hong-Tai Tzeng, and Ji-Yih Chen. "Signaling Pathways of Type I and Type III Interferons and Targeted Therapies in Systemic Lupus Erythematosus." Cells 8, no. 9 (August 23, 2019): 963. http://dx.doi.org/10.3390/cells8090963.
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Type I and type III interferons (IFNs) share several properties in common, including the induction of signaling pathways, the activation of gene transcripts, and immune responses, against viral infection. Recent advances in the understanding of the molecular basis of innate and adaptive immunity have led to the re-examination of the role of these IFNs in autoimmune diseases. To date, a variety of IFN-regulated genes, termed IFN signature genes, have been identified. The expressions of these genes significantly increase in systemic lupus erythematosus (SLE), highlighting the role of type I and type III IFNs in the pathogenesis of SLE. In this review, we first discussed the signaling pathways and the immunoregulatory roles of type I and type III IFNs. Next, we discussed the roles of these IFNs in the pathogenesis of autoimmune diseases, including SLE. In SLE, IFN-stimulated genes induced by IFN signaling contribute to a positive feedback loop of autoimmunity, resulting in perpetual autoimmune inflammation. Based on this, we discussed the use of several specific IFN blocking strategies using anti-IFN-α antibodies, anti-IFN-α receptor antibodies, and IFN-α-kinoid or downstream small molecules, which intervene in Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways, in clinical trials for SLE patients. Hopefully, the development of novel regimens targeting IFN signaling pathways will shed light on promising future therapeutic applications for SLE patients.
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Stone, Virginia M., Emma E. Ringqvist, Pär G. Larsson, Erna Domsgen, Ulrika Holmlund, Eva Sverremark-Ekström, and Malin Flodström-Tullberg. "Inhibition of Type III Interferon Expression in Intestinal Epithelial Cells—A Strategy Used by Coxsackie B Virus to Evade the Host’s Innate Immune Response at the Primary Site of Infection?" Microorganisms 9, no. 1 (January 5, 2021): 105. http://dx.doi.org/10.3390/microorganisms9010105.
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Increasing evidence highlights the importance of the antiviral activities of the type III interferons (IFNλs; IL-28A, IL-28B, IL29, and IFNλ4) in the intestine. However, many viruses have developed strategies to counteract these defense mechanisms by preventing the production of IFNs. Here we use infection models, a clinical virus isolate, and several molecular biology techniques to demonstrate that both type I and III IFNs induce an antiviral state and attenuate Coxsackievirus group B (CVB) replication in human intestinal epithelial cells (IECs). While treatment of IECs with a viral mimic (poly (I:C)) induced a robust expression of both type I and III IFNs, no such up-regulation was observed after CVB infection. The blunted IFN response was paralleled by a reduction in the abundance of proteins involved in the induction of interferon gene transcription, including TIR-domain-containing adapter-inducing interferon-β (TRIF), mitochondrial antiviral-signaling protein (MAVS), and the global protein translation initiator eukaryotic translation initiation factor 4G (eIF4G). Taken together, this study highlights a potent anti-Coxsackieviral effect of both type I and III IFNs in cells located at the primary site of infection. Furthermore, we show for the first time that the production of type I and III IFNs in IECs is blocked by CVBs. These findings suggest that CVBs evade the host immune response in order to successfully infect the intestine.
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Stoltz, Malin, and Jonas Klingström. "Alpha/Beta Interferon (IFN-α/β)-Independent Induction of IFN-λ1 (Interleukin-29) in Response to Hantaan Virus Infection." Journal of Virology 84, no. 18 (June 30, 2010): 9140–48. http://dx.doi.org/10.1128/jvi.00717-10.
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ABSTRACT Type III interferons ([IFNs]IFN-λ and interleukin-28 and -29 [IL-28/29]) are recently recognized cytokines with innate antiviral effects similar to those of type I IFNs (IFN-α/β). Like IFN-α/β, IFN-λ-expression can be induced by viruses, and it is believed that type I and III IFNs are regulated in the same manner. Hantaviruses are weak IFN-α/β inducers and have surprisingly been shown to activate IFN-α/β-independent IFN-stimulated gene (ISG) expression. Here, we show that in Hantaan virus (HTNV)-infected human epithelial A549 cells, induction of IFN-λ1 preceded induction of MxA and IFN-β by 12 and 24 h, respectively, and IFN-α was not induced at all. Furthermore, induction of IFN-λ1 and MxA was observed in HTNV-infected African green monkey epithelial Vero E6 cells, a cell line that cannot produce type I IFNs, clearly showing that HTNV can induce IFN-λ1 and ISGs in the complete absence of IFN-α/β. In HTNV-infected human fibroblast MRC-5 cells, which lack the IFN-λ receptor, induction of MxA coincided in time with IFN-β-induction. UV-inactivated HTNV did not induce any IFNs or MxA in any cell line, showing that activation of IFN-λ1 is dependent on replicating virus. Induction of both IFN-β and IFN-λ1 in A549 cells after poly(I:C)-stimulation was strongly inhibited in HTNV-infected cells, suggesting that HTNV can inhibit signaling pathways used to simultaneously activate types I and III IFNs. In conclusion, we show that HTNV can cause type I IFN-independent IFN-λ1 induction and IFN-λ1-specific ISG induction. Importantly, the results suggest the existence of specific signaling pathways that induce IFN-λ1 without simultaneous type I IFN induction during virus infection.
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Li, Shi-fang, Mei-jiao Gong, Fu-rong Zhao, Jun-jun Shao, Yin-li Xie, Yong-guang Zhang, and Hui-yun Chang. "Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection." Cellular Physiology and Biochemistry 51, no. 5 (2018): 2377–96. http://dx.doi.org/10.1159/000495897.
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The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.
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Ning, Fei, Xiaoyu Li, Li Yu, Bin Zhang, Yuna Zhao, Yu Liu, Baohong Zhao, Yingli Shang, and Xiaoyu Hu. "Hes1 attenuates type I IFN responses via VEGF-C and WDFY1." Journal of Experimental Medicine 216, no. 6 (April 23, 2019): 1396–410. http://dx.doi.org/10.1084/jem.20180861.
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Induction of type I interferons (IFNs) is critical for eliciting competent immune responses, especially antiviral immunity. However, uncontrolled IFN production contributes to pathogenesis of autoimmune and inflammatory diseases. We found that transcription factor Hes1 suppressed production of type I IFNs and expression of IFN-stimulated genes. Functionally, Hes1-deficient mice displayed a heightened IFN signature in vivo, mounted enhanced resistance against encephalomyocarditis virus infection, and showed signs of exacerbated experimental lupus nephritis. Mechanistically, Hes1 did not suppress IFNs via direct transcriptional repression of IFN-encoding genes. Instead, Hes1 attenuated activation of TLR upstream signaling by inhibition of an adaptor molecule, WDFY1. Genome-wide assessment of Hes1 occupancy revealed that suppression of WDFY1 was secondary to direct binding and thus enhancement of expression of VEGF-C by Hes1, making Vegfc a rare example of an Hes1 positively regulated gene. In summary, these results identified Hes1 as a homeostatic negative regulator of type I IFNs for the maintenance of immune balance in the context of antiviral immunity and autoimmune diseases.
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Utay, Netanya Sandler, and Daniel C. Douek. "Interferons and HIV Infection: The Good, the Bad, and the Ugly." Pathogens and Immunity 1, no. 1 (July 6, 2016): 107. http://dx.doi.org/10.20411/pai.v1i1.125.
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Whether type I interferons (IFNs) hinder or facilitate HIV disease progression is controversial. Type I IFNs induce the production of restriction factors that protect against mucosal HIV/SIV acquisition and limit virus replication once systemic infection is established. However, type I IFNs also increase systemic immune activation, a predictor of poor CD4+ T-cell recovery and progression to AIDS, and facilitate production and recruitment of target CD4+ T cells. In addition, type I IFNs induce CD4+ T-cell apoptosis and limit antigen-specific CD4+ and CD8+ T-cell responses. The outcomes of type I IFN signaling may depend on the timing of IFN-stimulated gene upregulation relative to HIV exposure and infection, local versus systemic type I IFN-stimulated gene expression, and the subtype of type I IFN evaluated. To date, most interventional studies have evaluated IFNa2 administration largely in chronic HIV infection, and few have evaluated the effects on tissues or the HIV reservoir. Thus, whether the effect of type I IFN signaling on HIV disease is good, bad, or so complicated as to be ugly remains a topic of hot debate.
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Dorrington, Michael G., Clinton J. Bradfield, Justin B. Lack, Bin Lin, Jonathan J. Liang, Tregei Starr, Orna Ernst, et al. "Type I IFNs facilitate innate immune control of the opportunistic bacteria Burkholderia cenocepacia in the macrophage cytosol." PLOS Pathogens 17, no. 3 (March 8, 2021): e1009395. http://dx.doi.org/10.1371/journal.ppat.1009395.
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The mammalian immune system is constantly challenged by signals from both pathogenic and non-pathogenic microbes. Many of these non-pathogenic microbes have pathogenic potential if the immune system is compromised. The importance of type I interferons (IFNs) in orchestrating innate immune responses to pathogenic microbes has become clear in recent years. However, the control of opportunistic pathogens–and especially intracellular bacteria–by type I IFNs remains less appreciated. In this study, we use the opportunistic, Gram-negative bacterial pathogen Burkholderia cenocepacia (Bc) to show that type I IFNs are capable of limiting bacterial replication in macrophages, preventing illness in immunocompetent mice. Sustained type I IFN signaling through cytosolic receptors allows for increased expression of autophagy and linear ubiquitination mediators, which slows bacterial replication. Transcriptomic analyses and in vivo studies also show that LPS stimulation does not replicate the conditions of intracellular Gram-negative bacterial infection as it pertains to type I IFN stimulation or signaling. This study highlights the importance of type I IFNs in protection against opportunistic pathogens through innate immunity, without the need for damaging inflammatory responses.
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Stegelmeier, Ashley A., Maedeh Darzianiazizi, Kiersten Hanada, Shayan Sharif, Sarah K. Wootton, Byram W. Bridle, and Khalil Karimi. "Type I Interferon-Mediated Regulation of Antiviral Capabilities of Neutrophils." International Journal of Molecular Sciences 22, no. 9 (April 29, 2021): 4726. http://dx.doi.org/10.3390/ijms22094726.
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Interferons (IFNs) are induced by viruses and are the main regulators of the host antiviral response. They balance tissue tolerance and immune resistance against viral challenges. Like all cells in the human body, neutrophils possess the receptors for IFNs and contribute to antiviral host defense. To combat viruses, neutrophils utilize various mechanisms, such as viral sensing, neutrophil extracellular trap formation, and antigen presentation. These mechanisms have also been linked to tissue damage during viral infection and inflammation. In this review, we presented evidence that a complex cross-regulatory talk between IFNs and neutrophils initiates appropriate antiviral immune responses and regulates them to minimize tissue damage. We also explored recent exciting research elucidating the interactions between IFNs, neutrophils, and severe acute respiratory syndrome-coronavirus-2, as an example of neutrophil and IFN cross-regulatory talk. Dissecting the IFN-neutrophil paradigm is needed for well-balanced antiviral therapeutics and development of novel treatments against many major epidemic or pandemic viral infections, including the ongoing pandemic of the coronavirus disease that emerged in 2019.
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Papinska, J., H. Bagavant, G. B. Gmyrek, M. Sroka, S. Tummala, K. A. Fitzgerald, and U. S. Deshmukh. "Activation of Stimulator of Interferon Genes (STING) and Sjögren Syndrome." Journal of Dental Research 97, no. 8 (March 5, 2018): 893–900. http://dx.doi.org/10.1177/0022034518760855.
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Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-γ, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.