IFN Type Research Articles

Toll-Like Receptor 4, but Not Neutrophil Extracellular Traps, Promote IFN Type I Expression to Enhance Th2 Responses to Nippostrongylus brasiliensis.

The induction of Th2 responses is thought to be multifactorial, and emerge from specific pathways distinct from those associated with antagonistic antibacterial or antiviral Th1 responses. Here, we show that the recognition of non-viable Nippostrongylus brasiliensis (Nb) in the skin induces a strong recruitment of monocytes and neutrophils and the release of neutrophil extracellular traps (NETs). Nb also activates toll-like receptor 4 (TLR4) signaling with expression of Ifnb transcripts in the skin and the development of an IFN type I signature on helminth antigen-bearing dendritic cells in draining lymph nodes. Co-injection of Nb together with about 10,000 Gram-negative bacteria amplified this TLR4-dependent but NET-independent IFN type I response and enhanced the development of Th2 responses. Thus, a limited activation of antibacterial signaling pathways is able to boost antihelminthic responses, suggesting a role for bacterial sensing in the optimal induction of Th2 immunity.

Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis

Peripheral serotonin (5-hydroxytryptamine, 5-HT) regulates cell growth and differentiation in numerous cell types through engagement of seven types of cell surface receptors (HTR1–7). Deregulated 5-HT/HTR levels contribute to pathology in chronic inflammatory diseases, with macrophages being relevant targets for the physio-pathological effects of 5-HT. In fact, 5-HT skews human macrophage polarization through engagement of 5-HT2BR and 5-HT7R receptors. We now report that 5-HT primes macrophages for reduced pro-inflammatory cytokine production and IFN type I-mediated signaling, and promotes an anti-inflammatory and pro-fibrotic gene signature in human macrophages. The acquisition of the 5-HT-dependent gene profile primarily depends on the 5-HT7R receptor and 5-HT7R-initiated PKA-dependent signaling. In line with the transcriptional results, 5-HT upregulates TGFβ1 production by human macrophages in an HTR7- and PKA-dependent manner, whereas the absence of Htr7 in vivo results in diminished macrophage infiltration and collagen deposition in a mouse model of skin fibrosis. Our results indicate that the anti-inflammatory and pro-fibrotic activity of 5-HT is primarily mediated through the 5-HT7R-PKA axis, and that 5-HT7R contributes to pathology in fibrotic diseases.

P.197 - Myogenic progenitor cells exhibit IFN type I-driven pro-angiogenic properties and molecular signature during juvenile dermatomyositis

Juvenile DermatoMyositis (JDM) is an inflammatory pediatric myopathy characterized by focal capillary loss in muscle, followed by a progressive recovery upon adequate immunomodulating treatments, although some patients remain refractory to treatments. While the underlying mechanism of capillary depletion remains uncertain, recent studies have identified an upregulation of type I Interferon (IFN-I) expression specific to JDM. Given that myogenic precursor cells (MPCs) exert pro-angiogenic activity during normal skeletal muscle regeneration, we hypothesized that they may also modulate vascular remodeling /angiogenesis during JDM. Using human cell cocultures, we showed that the high angiogenic properties of MPCs of JDM patients, associated with the expression of an angiogenic molecular signature. Moreover, transcriptomic analysis of MPCs freshlyisolated from patient muscle identified IFN-I as the master regulator of the most upregulated genes in JDM-derived MPCs. Functionally, treatment of normal MPCs with IFN-I recapitulated the molecular pattern and the pro-angiogenic functions of JDM-derived MPCs. In vivo histological investigation showed that MPCs synthesized IFN-I and major pro-angiogenic molecules in JDM muscle. Moreover, MPCs derived from JDM muscles characterized by a strong vasculopathy produced higher levels of IFN-I, confirming MPCs as a cellular source of IFN-I during JDM, that correlated with the severity of the disease. These results demonstrate a new IFN-I pathway in JDM, which activates in an autocrine/paracrine way the production of angiogenic effectors by MPCs, triggering their pro-angiogenic function to promote vessel recovery and muscle reconstruction.

Expression pattern of TRIM genes in bovine macrophages stimulated with PAMPs

Abstract In mammals innate immune mechanisms form the first line of defence against invading pathogens. Detection of viruses early in infection relies on intracellular receptors that sense microbial molecular patterns, subsequently leading to gene transcription that eventually produces IFN type I and II. Type I and II IFNs act to prevent replication of viruses. Tripartite Motif-containing (TRIM) proteins belong to a superfamily of RING-domain E3 ubiquitin ligases. They represent a novel class of antiviral molecules involved in innate immunity. These enzymes function in a wide variety of important cellular processes, particularly in innate antiviral response mechanisms. We studied the expression profile of 46 TRIM genes in a bovine macrophage cell line BoMac using RT2 PCR. PAMPs were used to imitate 2 important groups of pathogens. PolyI:C was used in place of viral dsRNA, LPS was used in place of Gram-negative bacteria, Pam3CSK4 was used in place of Gram-positive and negative bacteria, PolyI:C-LyoVec was used in place of viral sRNA and CpG was used in place of bacterial and viral DNA. Of the 46 TRIM genes, only 8 bovine TRIM genes were upregulated following stimulation of BoMac with individual PAMPs. PolyI:C induce upregulation of TRIM21, TRIM25 and TRIM56. All three TRIMs are known for their antiviral activity in human cell lines and mice. Pam3CSK4 and LPS, both upregulated TRIM10. PolyI:C-LyoVec upregulated TRIM9, TRIM40 and TRIM55. TRIM40 is an anti-inflammatory molecule. CpG upregulated TRIM40 and TRIM29. High expression of TRIM29 is regarded as a poor prognostic in many tumors, but no antimicrobial role has been described yet for TRIM29. Data will be discussed in the context of antiviral role of TRIMs in bovine viral infections.

IFN type I and II induce BAFF secretion from human decidual stromal cells

B cell activating factor (BAFF) is a critical cytokine for maturation of immature B cells. In murine lymph nodes, BAFF is mainly produced by podoplanin-expressing stromal cells. We have previously shown that circulating BAFF levels are maximal at birth, and that farmers’ children exhibit higher BAFF levels in cord blood than non-farmers’ children. Here, we sought to investigate whether maternal-derived decidual stromal cells from placenta secrete BAFF and examine what factors could stimulate this production. We found that podoplanin is expressed in decidua basalis and in the underlying villous tissue as well as on isolated maternal-derived decidual stromal cells. Decidual stromal cells produced BAFF when stimulated with IFN-γ and IFN-α, and NK cells and NK-T-like cells competent of IFN-γ production were isolated from the decidua. Finally, B cells at different maturational stages are present in decidua and all expressed BAFF-R, while stromal cells did not. These findings suggest that decidual stromal cells are a cellular source of BAFF for B cells present in decidua during pregnancy.

Abstract B114: Innate immunity modulators to enhance oncolytic VSV-GP for the treatment of ovarian cancer

Abstract Oncolytic viruses (OV) that preferentially replicate in and kill tumor cells are promissing novel treatment option for advanced cancers. Through cell lysis, OV set tumor antigens free, which in combination with the OV adjuvant effect, unleashes a strong anti-tumor immune response. Here, we propose the use of the oncolytic VSV-GP for the treatment of ovarian cancer. Effective oncolytic activity of VSV-GP could be demonstrated in a panel of ovarian cancer cell lines. Analysis of the innate immune response of ovarian cancer cells to VSV-GP revealed IFN type I production and induction of an antiviral state of the cells as a potential mechanism leading to shortcomings in virotherapeutic treatment. In vivo, VSV-GP was tested in a subcutaneous ovarian cancer xenograft mouse model using the A2780 cell line. Treatment led to tumor remission, which was temporary in most mice resulting in tumor recurrance. In an orthotopic xenograft mouse model, intraperitoneal injection of the virus led to significantly prolonged survival compared to untreated animals. In addition, combination therapy of VSV-GP with the JAK1/2-inhibitor ruxolitinib was successfully tested in both models and found to enhance the oncolytic effect. The drug inhibited the signalling pathway induced by type I IFN and could thus be used to inhibit the antiviral innate immune response and enhance intratumoral viral replication. Importantly, despite inhibiting the antiviral response, no toxicity was observed in mice receiving up to 109 pfus (plaque forming units) VSV-GP via intraperitoneal application. In addition, using luciferase expressing VSV-GP, we found no off target tropism with ruxolitinib combination. In conclusion, VSV-GP was tested as a potent oncolytic virus to treat ovarian cancer. Restriction of viral replication due to the innate immune response could be overcome by the combination treatment of VSV-GP with the Jak-1/2 inhibitor ruxolitinib. Citation Format: Janine Kimpel, Carles R. Urbiola, Catherine Dold, Christian Marth, Alexander Muik, Dorothee Holm-von Laer, Guido Wollmann. Innate immunity modulators to enhance oncolytic VSV-GP for the treatment of ovarian cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B114.

Mechanism and role of MCP-1 upregulation upon chikungunya virus infection in human peripheral blood mononuclear cells.

Monocyte chemoattractant protein-1 (MCP-1/CCL2)-mediated migration of monocytes is essential for immunological surveillance of tissues. During chikungunya virus (CHIKV) infection however, excessive production of MCP-1 has been linked to disease pathogenesis. High MCP-1 serum levels are detected during the viremic phase of CHIKV infection and correlate with the virus titre. In vitro CHIKV infection was also shown to stimulate MCP-1 production in whole blood; yet the role and the mechanism of MCP-1 production upon infection of human peripheral blood mononuclear cells remain unknown. Here we found that active CHIKV infection stimulated production of MCP-1 in monocytes. Importantly however, we found that communication with other leukocytes is crucial to yield MCP-1 by monocytes upon CHIKV infection. Indeed, blocking interferon-α/β receptor or the JAK1/JAK2 signalling downstream of the receptor abolished CHIKV-mediated MCP-1 production. Additionally, we show that despite the apparent correlation between IFN type I, CHIKV replication and MCP-1, modulating the levels of the chemokine did not influence CHIKV infection. In summary, our data disclose the complexity of MCP-1 regulation upon CHIKV infection and point to a crucial role of IFNβ in the chemokine secretion. We propose that balance between these soluble factors is imperative for an appropriate host response to CHIKV infection.

IFN-λ cancer immunotherapy: new kid on the block.

Interferon-lambda (IFN-λ) is a new IFN type, related to IFN-α, that is commonly used in the clinic. However, significant side effects accompanying IFN-α treatment limit enthusiasm for IFN-α. In this review, we discuss the current landscape of IFN-α use in oncology and describe the biologic characteristics of IFN-λ. IFN-λ offers unique advantages, including a more tumor cell selective targeting, lower off-target binding and an ability to generate both innate and adaptive immune responses. IFN-λ has also demonstrated therapeutic benefit in murine cancer models. IFN-λ may be used in clinic as a single agent or in combination with other immunotherapy agents, such as immune checkpoint inhibitors. Further clinical trials will be needed to fully elucidate the potential of this novel agent in oncology.

DNA sensing via STING regulates immune responses in a lung cancer model via IDO

Abstract The Stimulator of Interferon Genes (STING) is a signaling adaptor associated with the endoplasmic reticulum. STING is activated by cytosolic DNA sensors to stimulate IFN type I expression (IFN-I). Recent reports revealed that DNA sensing to activate STING in dendritic cells (DCs) that engulfed dying tumor cells impeded growth of immunogenic tumors and potentiated responses to therapy. Consistent with these findings, synthetic STING agonists enhanced tumor regression. Paradoxically, Lewis Lung Carcinoma (LLC) grew slower in STING-deficient mice, revealing that STING is required for optimal LLC growth. Mechanistically, STING ablation abolished upregulation of the immunoregulatory enzyme, indoleamine 2,3 dioxygenase (IDO) in DCs located in tumor draining lymph nodes during LLC growth. Also, expression of the regulatory cytokine IL-10 and infiltration of myeloid derived suppressor cells (MDSCs) into the tumor microenvironment (TME) was diminished in mice lacking STING. In contrast, STING was not required for optimal growth of LLC tumors expressing neo-antigens, revealing a pivotal role for tumor antigenicity in influencing responses to DNA in the TME. These findings support the hypothesis that DNA from dying cells are sensed in the TME to activate STING, which induces dominant regulatory responses via IDO when tumor antigenicity is low and dominant immunogenic responses when tumor antigenicity is enhanced. Thus, cytosolic DNA sensing to activate STING has dichotomous roles in the TME, and tumor antigenicity is a pivotal factor influencing immune responses to DNA at sites of chronic inflammation associated with tumor growth.

Differences in Innate immune cell production of IFNα and IFNβ to cell activation in the Autoinflammatory Diseases CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) and SAVI (STING Associated Vasculopathy with Onset in Infancy)

Abstract The Type I IFN mediated autoinflammatory diseases SAVI and CANDLE are caused by gain-of-function mutations in Stimulator of Interferon Genes (STING) and loss-of-function mutations in proteasome components. We evaluated the innate immune cellular origin of IFN Type I in SAVI and CANDLE. We examined expression of IFN genes from FACS sorted T, B, NK and monocytes in SAVI (n=5) and CANDLE (n=3) normalized to healthy controls (HC). The Interquartile Range of Type I IFN expression was 78(4–151) and 481-fold(56-38,242) of IFNB1 and 60(3–116) and 0.4-fold(0.1–39) of IFNA7/IFNA17 in CANDLE and SAVI monocytes, respectively. Monocyte depletion reduced IFN message by 90% and FACS analysis confirmed that monocytes and not dendritic cells are the main source of IFNs. The overall mean ratio of IFNβ to IFNα was 989:1 in SAVI and 1.3:1 in CANDLE monocytes. Mean IFNα plasma levels measured by pan IFNα ELISA with 31pg/ml ±58 SEM in CANDLE and 230pg/ml ±112 SEM in SAVI. IP10 serum levels were 2215pg/ml ±702 SEM and 3632pg/ml ±860 SEM in CANDLE and SAVI, respectively. STING pathway activation with cGAMP in the presence of cycloheximide (CHX), a blocker of translational elongation, led to IFNB1 but not IFNA1, 2, 7, 17, 21 while CHX + epoxomicin, a proteasome inhibitor led to transcription of IFNAs and IFNB1 suggesting secondary upregulation of IFNAs in SAVI. Compared to healthy controls, CANDLE and SAVI had increased left-shifted immature CD13lo CD16+ neutrophils (9 and 4-fold, respectively), as well as higher expression of the activation marker CD36+ (6.9 and 6.9-fold, respectively) in total granulocytes. In conclusion, Type I IFN is mainly produced in monocytes and analyses of the IFN signaling in CANDLE and SAVI will allow us to develop improved targeted therapies.

Optineurin deficiency in mice is associated with increased sensitivity to Salmonella but does not affect proinflammatory NF-κB signaling.

Optineurin (OPTN) is an evolutionary conserved and ubiquitously expressed ubiquitin-binding protein that has been implicated in glaucoma, Paget bone disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. From in vitro studies, OPTN was shown to suppress TNF-induced NF-κB signaling and virus-induced IRF signaling, and was identified as an autophagy receptor required for the clearance of cytosolic Salmonella upon infection. To assess the in vivo functions of OPTN in inflammation and infection, we generated OPTN-deficient mice. OPTN knockout mice are born with normal Mendelian distribution and develop normally without any signs of spontaneous organ abnormality or inflammation. However, no differences in NF-κB activation could be observed in OPTN knockout mice or fibroblasts derived from these mice upon TNF or LPS treatment. Primary bone marrow-derived macrophages from OPTN-deficient mice had slightly impaired IRF signaling and reduced IFN type I production in response to LPS or poly(I,C). Finally, OPTN-deficient mice were more susceptible to infection with Salmonella, confirming in vivo the importance of OPTN in bacterial clearance.

Altered signaling in systemic juvenile idiopathic arthritis monocytes

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

Activation of Type I Interferon Signal Pathway in Patients with Multiple Sclerosis by the Russian Analog of β-Interferon-1b (transcriptional profiling data)

The introduction of Russian analogs of β-interferon (β-IFN) produced by recombinant strains of E. coli (β-IFN-1b) into medical practice in Russia for the pathogenetic treatment of multiple sclerosis (MS) requires, in accordance with contemporary standards, confirmation by transcriptome analysis that they activate the main signal pathways involved in the mechanism of action of β-IFN. In the present report we present such an analysis for Infibeta (produced by Generium). Whole-genome transcription profiling using an Illumina HT-12 microarray was performed to identify genes showing differential expression in peripheral blood mononuclear cells from MS patients in response to exposure to this agent. Comparison of the levels of gene expression in MS patients not previously treated with any kind of immunomodulatory therapy before and 10 h after the first dose of agent identified 490 genes whose expression showed statistically significant changes, of which 191 genes showed increases in expression (up-regulated genes) and 299 genes showed decreases in expression (down-regulated genes). These genes included genes from the inflammation system, the innate and adaptive immune systems, apoptosis, signal transmission, transcription, translation, and degradation. Analysis of the overall expression of sets (groups) of genes (gene set analysis) yielded data which may provide evidence that IFN type I signal pathway genes, as well as IFN-induced genes, are involved in patients’ responses to the agent. Thus, analysis by transcriptional profiling led to the conclusion that the mechanism of the immunomodulatory action of Infibeta is identical to that described for original β-IFN formulations.

The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis

BackgroundInterferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in...

ID: 73: Type I interferon-associated signaling in T cells: The novel functions of STING

The cytoplasmic protein Stimulator of Interferon Genes (STING) plays an essential role in sensing cytoplasmic DNA of intracellular pathogens and initiating IFN type I responses in myeloid cells. It can also directly bind cyclic dinucleotides produced by intracellular bacteria or by the DNA-binding cyclic GMP-AMP (cGAMP) synthase. To date, the signaling mechanisms involving STING activation has been studied in macrophages and dendritic cells. Taking into consideration the fact that STING is highly expressed in the thymus and spleen, we decided to investigate its functional role in T cells. We revealed that STING can be activated in T cells by DMXAA (5,6-dimethylxanthenone-4-acetic acid), which binds to the same site in murine STING as cGAMP and triggers phosphorylation of TBK1 and IRF3 resulting in IFNβ production and increased expression of interferon stimulated genes. In contrast to T lymphocytes obtained from C57B6 WT mice, STING−/− T cells displayed no phosphorylation of TBK1/IRF3, and produced no detectable IFNβ upon stimulation. DMXAA treatment also resulted in IFNgamma secretion by WT cells, while DMXAA-treated knockouts produced only a small amount of IFNgamma comparable to unstimulated WT T cells. Both CD4+ and CD8+ subsets of WT T cells responded to DMXAA with phosphorylation of TBK1/IRF3 and IFNβ production, but only CD4+ cells produced IFNgamma. By performing RNA sequencing, numerous differences in gene expression (including interferon stimulated genes) between WT and STING−/− T cells before and after DMXAA stimulation were identified. The work was supported by the Russian Science Foundation (grant no. 115-15-00100 ).

Newly recognized Mendelian disorders with rheumatic manifestations.

We review newly discovered monogenic immune-dysregulatory disorders that were reported in Pubmed over the last year. Fourteen novel monogenic immune-dysregulatory disorders that present with innate and acquired/adaptive immune dysregulation and inflammatory clinical phenotypes were identified. These include autosomal-dominant gain-of function mutations in viral innate immune sensors or their adaptors, TMEM173/STING IFIH1/MDA5 and DDX58/RIG-I that cause complex clinical syndromes distinct from IL-1-mediated diseases and present with a chronic type I interferon (IFN Type I) signature in peripheral blood. Gain-of-function mutations in NLRC4 add a novel inflammasome disorder associated with predisposition to macrophage-activation syndrome and highly elevated IL-18 levels. Mutations in ADA2, TRNT1 and COPA, AP1S3, and TNFRSF11A cause complex syndromes; loss-of-function mutations in enzymes and molecules are linked to the generation of 'cellular stress' and the release of inflammatory mediators that likely cause the inflammatory disease manifestations. A monogenic form of systemic-onset juvenile idiopathic arthritis is caused by homozygous mutations in LACC1. Lastly, mutations in PRKDC (recessive), STAT3, CTLA4, and PIK3R1 (all dominant) lead to impaired central and peripheral T-cell tolerance and present with variable disease manifestations of immunodeficiency and immune dysregulation/autoimmunity. A number of novel monogenic diseases that present with innate and/or acquired immune dysregulation reveal novel immune pathways that cause human inflammatory diseases and suggest potential novel targets for treatment.

Scanning for Therapeutic Targets within the Cytokine Network of Idiopathic Inflammatory Myopathies

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF), Interferons (IFNα/β/γ), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction.

NK cells require IL-28R for optimal in vivo activity

Natural killer (NK) cells are naturally circulating innate lymphoid cells that protect against tumor initiation and metastasis and contribute to immunopathology during inflammation. The signals that prime NK cells are not completely understood, and, although the importance of IFN type I is well recognized, the role of type III IFN is comparatively very poorly studied. IL-28R-deficient mice were resistant to LPS and cecal ligation puncture-induced septic shock, and hallmark cytokines in these disease models were dysregulated in the absence of IL-28R. IL-28R-deficient mice were more sensitive to experimental tumor metastasis and carcinogen-induced tumor formation than WT mice, and additional blockade of interferon alpha/beta receptor 1 (IFNAR1), but not IFN-γ, further enhanced metastasis and tumor development. IL-28R-deficient mice were also more susceptible to growth of the NK cell-sensitive lymphoma, RMAs. Specific loss of IL-28R in NK cells transferred into lymphocyte-deficient mice resulted in reduced LPS-induced IFN-γ levels and enhanced tumor metastasis. Therefore, by using IL-28R-deficient mice, which are unable to signal type III IFN-λ, we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.

Cytotoxic and antiviral properties of 4,4'-bis-aminoalkoxybiphenyls

Zanoza Svitlana O., Bykova Tatiana I., Lyakhov Sergey A., Andronati Sergey A., Zholobak Nadiya M., Levandovskiy Igor A. Cytotoxic and antiviral properties of 4,4'-bis-aminoalkoxybiphenyls. Journal of Health Sciences. 2014;4(16):276-281. ISSN 1429-9623 / 2300-665X. DOI 10.5281/zenodo.21774 http://dx.doi.org/10.5281/zenodo.21774 https://pbn.nauka.gov.pl/works/597257 POL - index https://pbn.nauka.gov.pl/polindex/browse/article/article-7b456720-fdc3-40eb-b04d-ecbde3966e51 http://journal.rsw.edu.pl/index.php/JHS/article/view/2014%3B4%2816%29%3A276-281 The journal has had 5 points in Ministry of Science and Higher Education of Poland parametric evaluation. Part B item 1089. (31.12.2014). © The Author (s) 2014; This article is published with open access at Licensee Open Journal Systems of Radom University in Radom, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 15.11.2014. Revised 05.12.2014. Accepted: 25.12.2014. CYTOTOXIC AND ANTIVIRAL PROPERTIES OF 4,4'-BIS-AMINOALKOXYBIPHENYLS Svitlana O. Zanoza 1 , Tatiana I. Bykova 2 , Sergey A. Lyakhov 1 , Sergey A. Andronati 1 , Nadiya M. Zholobak 2 , Igor A. Levandovskiy 3 1 O.V. Bogatsky Physico-Chemical Institute of the National Academy of Sciences of Ukraine, 86 Lustdorfska Doroga, 65080, Odesa, Ukraine. E-mail sa.zanoza@gmail.com 2 D.K. Zabolotny Institute of Microbiology and Virology of the NASU, 154D Acad. Zabolotny str., 03680, Kyiv, Ukraine. E-mail bti77@ukr.net 3 Department of Organic Chemistry, National Technical University of Ukraine, Pr. Pobedy 37, 03056 Kyiv, Ukraine. E-mail lia@xtf.kpi.ua Summary Despite the high efficiency of the etiotropic antiviral drugs and antiviral vaccines they can lead to the selection of resistant mutant variants, initiate of evolutionary arms race [1] and pose a threat of the superinfections and epidemics. In this regard, the creation of means that enhance non-specific antiviral resistance is actual task and will be such in the future. The development of such agents – the functional analogues of amixyne (tilorone) – inducers of IFN type I is conducted in the past decades in O.V. Bogatsky Physico-Chemical Institute of the National Academy of Sciences of Ukraine. As an inactive model compound 4,4'-bis-[2-(diethylamino)ethoxy]bi-phenyl was synthesized in 2005 and unexpectedly appeared as an active antiviral and interferon inductor [2]. In this regard, analogues of this compound is of considerable interest from the point of view of the structure-properties relationships. These substances (R-A-4DP4-A-R, R – amino group of different structure; A = -(CH 2 ) n O-, n = 2 - 6; 4BP4 - 4,4'-biphenyl) were synthesized via halogenoalkylation of 4,4-dioxybiphenyl with dihalogenoalkanes following with amino dehalogenation. Keywords : Cytotoxic; antiviral properties; aminoalkoksybiphenyls.

HTLV-1 Tax protein recruitment into IKKε and TBK1 kinase complexes enhances IFN-I expression

The Tax protein expressed by human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in the deregulation of cellular pathways involved in the immune response, inflammation, cell survival, and cancer. Many of these effects derive from Tax multiple interactions with host factors, including the subunits of the IKK-complex that are required for NF-κB activation. IKKɛ and TBK1 are two IKK-related kinases that allow the phosphorylation of interferon regulatory factors that trigger IFN type I gene expression. We observed that IKKɛ and TBK1 recruit Tax into cellular immunocomplexes. We also found that TRAF3, which regulates cell receptor signaling effectors, forms complexes with Tax. Transactivation analyses revealed that expression of Tax, in presence of IKKɛ and TBK1, enhances IFN-β promoter activity, whereas the activation of NF-κB promoter is not modified. We propose that Tax may be recruited into the TBK1/IKKɛ complexes as a scaffolding-adaptor protein that enhances IFN-I gene expression.