Interferon Family Research Articles

Inflammatory gene expression profiling in peripheral blood from patients with Alzheimer's disease reveals key pathways and hub genes with potential diagnostic utility: a preliminary study.

BackgroundAlzheimer’s disease (AD) is an age-related neurodegenerative disease caused by central nervous system disorders. Late-onset Alzheimer disease (LOAD) is the most common neurodegenerative disorder worldwide. Differences at the expression level of certain genes, resulting from either genetic variations or environmental interactions, might be one of the mechanisms underlying differential risks for developing AD. Peripheral blood genome transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tau for AD research.MethodsThis preliminary study explores molecular pathogenesis of LOAD-related inflammation through next generation sequencing, to assess RNA expression profiles in peripheral blood from five patients with LOAD and 10 healthy controls.ResultsThe analysis of RNA expression profiles revealed 94 genes up-regulated and 147 down-regulated. Gene function analysis, including Gene Ontology (GO) and KOBAS-Kyoto Encyclopedia of DEGs and Genomes (KEGG) pathways indicated upregulation of interferon family (INF) signaling, while the down-regulated genes were mainly associated with the cell cycle process. KEGG metabolic pathways mapping showed gene expression alterations in the signaling pathways of JAK/STAT, chemokines, MAP kinases and Alzheimer disease. The results of this preliminary study provided not only a comprehensive picture of gene expression, but also the key processes associated with pathology for the regulation of neuroinflammation, to improve the current mechanisms to treat LOAD.

Deleterious single nucleotide polymorphisms (SNPs) of human IFNAR2 gene facilitate COVID-19 severity in patients: a comprehensive in silico approach

In humans, the dimeric receptor complex IFNAR2-IFNAR1 accelerates cellular response triggered by type I interferon (IFN) family proteins in response to viral infection including Coronavirus infection. Studies have revealed the association of the IFNAR2 gene with severe illness in Coronavirus infection and indicated the association of genomic variants, i.e. single nucleotide polymorphisms (SNPs). However, comprehensive analysis of SNPs of the IFNAR2 gene has not been performed in both coding and non-coding region to find the causes of loss of function of IFNAR2 in COVID-19 patients. In this study, we have characterized coding SNPs (nsSNPs) of IFNAR2 gene using different bioinformatics tools and identified deleterious SNPs. We found 9 nsSNPs as pathogenic and disease-causing along with a decrease in protein stability. We employed molecular docking analysis that showed 5 nsSNPs to decrease binding affinity to IFN. Later, MD simulations showed that P136R mutant may destabilize crucial binding with the IFN molecule in response to COVID-19. Thus, P136R is likely to have a high impact on disrupting the structure of the IFNAR2 protein. GTEx portal analysis predicted 14 sQTLs and 5 eQTLs SNPs in lung tissues hampering the post-transcriptional modification (splicing) and altering the expression of the IFNAR2 gene. sQTLs and eQTLs SNPs potentially explain the reduced IFNAR2 production leading to severe diseases. These mutants in the coding and non-coding region of the IFNAR2 gene can help to recognize severe illness due to COVID 19 and consequently assist to develop an effective drug against the infection. Communicated by Ramaswamy H. Sarma

Development of antigen sandwich ELISA to detect interferon-alpha (IFN-α) using monoclonal antibodies in chicken

Abstract Interferon alpha (IFN-α) belongs to the type I interferon family which mediates an early innate immune response to viral infections. In the present study, we developed a sandwich ELISA using specific mouse monoclonal antibodies (mAbs) to measure IFN-α production in chickens. Recombinant chicken IFN-α (chIFN-α) expressed in yeast was used to immunize the mice. Five mAbs which specifically recognize chIFN-α antigen were selected and characterized. For sandwich ELISA development, mAbs were labeled with biotin, followed by a pairing assay to identify the best capture and detection antibodies. Two sets of mouse anti-chIFN-α mAb pairs were identified as optimum pairs of antibodies for detection of chIFN-α. The sandwich ELISA effectively detected native chicken IFN-α in chicken macrophage cells stimulated by polyinosinic:polycytidylic acid and its minimum detectable level was about 25 pg/mL. The anti-viral activity of chIFN-α against vesicular stomatitis virus (VSV) was evaluated in chicken embryonic fibroblast and the mouse anti-chIFN-α mAbs which neutralize the activity of chicken IFN-α against VSV were identified. The newly developed antigen capture sandwich ELISA for the detection of chIFN-α will be a useful tool to monitor IFN-α production in chickens during viral infections.

Interferon-Lambda: A Key Cytokine for Dendritic Cell Development?

Abstract In light of the current pandemic, COVID-19, our understanding of how the immune system combats viral infection has become more important than ever. Interferons (IFNs) are an integral component of the immune system’s anti-viral response. While the functions of Type I Interferons have been extensively studied, the newest member of the Interferon family, Interferon-Lambda (IFN-λ), is yet to be fully investigated. Currently, it is believed that the canonical signalling pathway of the IFN-λ receptor (R, defined as IFN-λR1 and IL-10Rb) is shared with Type I IFN-αR signalling and leads to the transcription of Interferon Stimulated Genes (ISGs), key genes involved in antiviral immunity. However, there is a growing body of evidence that indicates that IFN-λR1 is involved in signalling pathways that differ to IFN-αR. Notably amongst this evidence is IFN-λR1’s restricted expression to epithelial and some haematopoietic cells as well as non-redundant roles being discovered at mucosal barriers. Building on novel preliminary data, this project seeks to differentiate IFN-λR1 signalling from this canonical pathway and determine whether other receptor chains are involved. Dendritic Cells (DCs), key mediators linking innate and adaptive immunity, are the focus of this project as they are major producers of IFN-λ and are also one of the few haematopoietic cells which express IFN-λR1. Using DCs, this project will investigate the signalling pathways regulated by IFN-λR1 and other potential pathways instigated by the interaction between IFN-λR1 and other receptors. Additionally, this work will focus on how IFN-λ signalling contributes to cellular function in the context of DC differentiation and development.

Interferon-Gene Family Alterations Following the SARS-Cov Infection in Association with Iron Metabolism and Lymphoid Biology

Interferon (IFN) family has a significant impact on both SARS-CoV and SARS-CoV-2. The aim of this current bioinformatics study is to assess IFN-gene family alterations following the SARS-CoV infection in association with the iron metabolism and lymphoid biology.Gene expression data of human bronchial epithelial cells treated with SARS-CoV for 12, 24, 48 hours were obtained from Array Express (GSE17400). In order to use the obtained data in other targeted analyses,the raw data were normalized by robust multisequence analysis in accordance with the procedure in the Affy package in R. These data consist of 23344 genes (54675 probe sets). In addition, each gene has three repeated expression data values for 12, 24, 48 hours, respectively. For the 48 hours group,positive regulations of the natural killer (NK) cell activation and NK cell-mediated cytotoxicity, as well as hematopoietic stem cells proliferation,were found to be more significant regard to their nominal p-value, family-wise error rate, and false discovery rate (q-value) calculated by gen set enrichment analysis. The gene sets with nominal (NOM) p-value 0.8) with exposure time to the virus. These results suggest that hematopoietic stem cell proliferation pathway is affected by the viral SARS-CoV infection.

Positive natural selection in primate\xa0genes of the type I interferon response

BackgroundThe Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one.ResultsWe curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid.ConclusionViruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

Comparative Transcriptome Profiling of Human and Pig Intestinal Epithelial Cells after Porcine Deltacoronavirus Infection.

Porcine deltacoronavirus (PDCoV) is an emerging infectious disease of swine with zoonotic potential. Phylogenetic analysis suggests that PDCoV originated recently from a host-switching event between birds and mammals. Little is known about how PDCoV interacts with its differing hosts. Human-derived cell lines are susceptible to PDCoV infection. Herein, we compare the gene expression profiles of an established host swine cells to potential emerging host human cells after infection with PDCoV. Cell lines derived from intestinal lineages were used to reproduce the primary sites of viral infection in the host. Porcine intestinal epithelial cells (IPEC-J2) and human intestinal epithelial cells (HIEC) were infected with PDCoV. RNA-sequencing was performed on total RNA extracted from infected cells. Human cells exhibited a more pronounced response to PDCoV infection in comparison to porcine cells with more differentially expressed genes (DEGs) in human, 7486, in comparison to pig cells, 1134. On the transcriptional level, the adoptive host human cells exhibited more DEGs in response to PDCoV infection in comparison to the primary pig host cells, where different types of cytokines can control PDCoV replication and virus production. Key immune-associated DEGs and signaling pathways are shared between human and pig cells during PDCoV infection. These included genes related to the NF-kappa-B transcription factor family, the interferon (IFN) family, the protein-kinase family, and signaling pathways such as the apoptosis signaling pathway, JAK-STAT signaling pathway, inflammation/cytokine–cytokine receptor signaling pathway. MAP4K4 was unique in up-regulated DEGs in humans in the apoptosis signaling pathway. While similarities exist between human and pig cells in many pathways, our research suggests that the adaptation of PDCoV to the porcine host required the ability to down-regulate many response pathways including the interferon pathway. Our findings provide an important foundation that contributes to an understanding of the mechanisms of PDCoV infection across different hosts. To our knowledge, this is the first report of transcriptome analysis of human cells infected by PDCoV.

The Dramatic Role of IFN Family in Aberrant Inflammatory Osteolysis.

Skeletal system has been considered a highly dynamic system, in which bone-forming osteoblasts and bone-resorbing osteoclasts go through a continuous remodeling cycle to maintain homeostasis of bone matrix. It has been well acknowledged that interferons (IFNs), acting as a subgroup of cytokines, not only have crucial effects on regulating immunology but also could modulate the dynamic balance of bone matrix. In the light of different isoforms, IFNs have been divided into three major categories in terms of amino acid sequences, recognition of specific receptors and biological activities. Currently, type I IFNs consist of a multi-gene family with several subtypes, of which IFN-α exerts pro-osteoblastogenic effects to activate osteoblast differentiation and inhibits osteoclast fusion to maintain bone matrix integrity. Meanwhile, IFN-β suppresses osteoblast-mediated bone remodeling as well as exhibits inhibitory effects on osteoclast differentiation to attenuate bone resorption. Type II IFN constitutes the only type, IFN-γ, which exerts regulatory effects on osteoclastic bone resorption and osteoblastic bone formation by biphasic ways. Interestingly, type III IFNs are regarded as new members of IFN family composed of four members, including IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4, which have been certified to participate in bone destruction. However, the direct regulatory mechanisms underlying how type III IFNs modulate the metabolic balance of bone matrix, remains poorly elucidated. In this review, we have summarized functions of IFN family during physiological and pathological conditions and described the mechanisms by which IFNs maintain bone matrix homeostasis via affecting the osteoclast-osteoblast crosstalk. In addition, the potential therapeutic effects of IFNs on inflammatory bone destruction diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and infectious bone diseases are also well displayed, which are based on the predominant role of IFNs in modulating the dynamic equilibrium of bone matrix.

The Role of Structure in the Biology of Interferon Signaling.

Interferons (IFNs) are a family of cytokines with the unique ability to induce cell intrinsic programs that enhance resistance to viral infection. Induction of an antiviral state at the cell, tissue, organ, and organismal level is performed by three distinct IFN families, designated as Type-I, Type-II, and Type-III IFNs. Overall, there are 21 human IFNs, (16 type-I, 12 IFNαs, IFNβ, IFNϵ, IFNκ, and IFNω; 1 type-II, IFNγ; and 4 type-III, IFNλ1, IFNλ2, IFNλ3, and IFNλ4), that induce pleotropic cellular activities essential for innate and adaptive immune responses against virus and other pathogens. IFN signaling is initiated by binding to distinct heterodimeric receptor complexes. The three-dimensional structures of the type-I (IFNα/IFNAR1/IFNAR2), type-II (IFNγ/IFNGR1/IFNGR2), and type-III (IFNλ3/IFNλR1/IL10R2) signaling complexes have been determined. Here, we highlight similar and unique features of the IFNs, their cell surface complexes and discuss their role in inducing downstream IFN signaling responses.

Jak infekcje i cytokiny wpływają na sen i zachowanie człowieka i zwierząt?

Produkowane podczas reakcji zapalnej cytokiny pro-zapalne (IL-1b, IL-6, TNFa) i prostagandyny (np. PGE2) regulują aktywność leukocytów i pobudzają produkcję białek ostrej fazy np. CRP. Oddziałują także na na różne struktury mózgu i wywołują szereg zmian behawioralnych łącznie opisywanych jako zachowania chorobowe (ang. sickness behavior). Składa się ma nie między innymi gorączka, zaburzenia łaknienia, aktywności lokomotorycznej i poznawczej oraz zaburzenia struktury i długości snu. Najczęściej ich działanie powoduje skrócenie fazy zasypiania i fazy snu paradoksalnego (REM) oraz wydłużenie fazy snu wolnofalowego (SWS). Podobne działanie mają także IL-2 i cytokiny należące do rodziny interferonów, w tym najważniejsze dla odpowiedzi przeciwirusowej ? interferony typu I (IFN I). Kierunek i nasilenie tych zmian zależą od fazy i nasilenia infekcji.
 Indukowane przez cytokiny pro-zapalne zmiany behawioralne są wysoce adaptacyjne i konserwatywne ewolucyjnie.

A Novel Type-I Interferon Family, Bovine Interferon-Chi, Is Involved in Positive-Feedback Regulation of Interferon Production.

Interferon-chi (IFN-χ) is a type of function-unknown IFN. IFN-χ in bovines (BoIFN-χ) has evolved as a multigene family. This family comprises four IFN-χ subtypes, two of which are functional genes, which we demonstrated to (i) have antiviral and antiproliferative activities, (ii) be highly sensitive to trypsin, and (iii) remain stable with changes in pH and temperature. BoIFN-χ is a key intermediate in antiviral response, PAbs against BoIFN-χs could downregulate the transcriptional activation of ISGs induced by poly(I:C), and BoIFN-χs could be induced upon virus infection at the early and late phase. Additionally, BoIFN-χs bind with type-I IFN receptors, induce transcription of interferon regulatory factor 7 (IRF7), interferon-stimulated genes (ISGs), and type-I IFNs as well as myxovirus resistance protein 1 (Mx1) expression. Expression of ISGs and activation of IFN-stimulated response element (ISRE) induced with BoIFN-χs could be downregulated significantly by the Janus kinase (JAK) 1 and signal transducers and activators of transcription (STAT) 1 inhibitor. The promoters of BoIFN-β, nuclear factor-kappa B, and ISRE could be activated with BoIFN-χs, and the BoIFN-χ promoter could be activated by other type-I IFNs. Overall, BoIFN-χ could be induced with virus infection and signal through the JAK-STAT pathway to form a positive-feedback regulation of IFN production. These findings may facilitate further research on the role of IFN-χ in innate immune responses.

Insights Into Type I and III Interferons in Asthma and Exacerbations

Asthma is a highly prevalent, chronic respiratory disease that impacts millions of people worldwide and causes thousands of deaths every year. Asthmatics display different phenotypes with distinct genetic components, environmental causes, and immunopathologic signatures, and are broadly characterized into type 2-high or type 2-low (non-type 2) endotypes by linking clinical characteristics, steroid responsiveness, and molecular pathways. Regardless of asthma severity and adequate disease management, patients may experience acute exacerbations of symptoms and a loss of disease control, often triggered by respiratory infections. The interferon (IFN) family represents a group of cytokines that play a central role in the protection against and exacerbation of various infections and pathologies, including asthma. Type I and III IFNs in particular play an indispensable role in the host immune system to fight off pathogens, which seems to be altered in both pediatric and adult asthmatics. Impaired IFN production leaves asthmatics susceptible to infection and with uncontrolled type 2 immunity, promotes airway hyperresponsiveness (AHR), and inflammation which can lead to asthma exacerbations. However, IFN deficiency is not observed in all asthmatics, and alterations in IFN expression may be independent of type 2 immunity. In this review, we discuss the link between type I and III IFNs and asthma both in general and in specific contexts, including during viral infection, co-infection, and bacterial/fungal infection. We also highlight several studies which examine the potential role for type I and III IFNs as asthma-related therapies.

Development of antigen sandwich ELISA to detect interferon-alpha (IFN-α) using monoclonal antibodies in chicken

Interferon alpha (IFN-α) belongs to the type I interferon family which mediates an early innate immune response to viral infections. In the present study, we developed sandwich ELISA using specific mouse monoclonal antibodies (mAbs) to measure IFN-α production in chickens. Recombinant chicken IFN-α (chIFN-α) expressed in yeast were purchased from Kingfisher Biotech, and used to immunize the mice. Five mAbs which specifically recognize chicken IFN-α antigen were selected and characterized. For sandwich ELISA development, mAbs were labeled with biotin, followed by a pairing test to identify the best capture and detection antibodies. Two sets of mouse anti-chIFN-α mAb pairs were determined and a standard curve was established using recombinant chIFN-α. The sandwich ELISA effectively detected an increased IFN-α production in chicken macrophage cells stimulated by polyinosinic:polycytidylic acid (poly I:C), and its minimum detectable level was about 25 pg/mL. The anti-viral activity of chIFN-α against vesicular stomatitis virus was characterized in avian embryonic fibroblast and the mouse anti-chIFN-α mAbs which neutralize its activity were identified. The newly developed antigen sandwich ELISA developed in this study will be a useful tool to monitor IFN-α production in chickens.

Oligoadenylate Synthetases 1 Enhances DNA Sensor Cgas Translation to Mediate Antiviral Activity

Oligoadenylate synthetases (OAS) are a family of interferon (IFN)-stimulated genes known to inhibit viral replication through the enzymatic synthesis of 2'-5' oligoadenylates and activation of Ribonuclease L. However, this canonical mechanism does not explain the antiviral properties of enzymatically inactive OAS proteins. Here we describe an enzyme activity-independent function of OAS1 that restricts West Nile virus (WNV) growth. The human OAS1 P46 isoform, generated by alternative splicing of the G allele of rs10774671 SNP, upregulates translation of specific host mRNA including the DNA-sensor cGAS. Increased cGAS expression by OAS1 P46 augments the type I IFN response and inhibits WNV infection. A mouse Oas1 gene, Oas1b, also inhibits WNV growth through a similar mechanism. Specific residues in the RNA binding domains of P46 and Oas1b that regulate association of cGAS mRNA with OAS1, also control the antiviral activity. Our findings explain how some enzymatically inactive OAS1 proteins function as antiviral molecules.

Selective Interferon Responses of Intestinal Epithelial Cells Minimize Tumor Necrosis Factor Alpha Cytotoxicity.

Interferon (IFN) family cytokines stimulate genes (interferon-stimulated genes [ISGs]) that are integral to antiviral host defense. Type I IFNs act systemically, whereas type III IFNs act preferentially at epithelial barriers. Among barrier cells, intestinal epithelial cells (IECs) are particularly dependent on type III IFN for the control and clearance of virus infection, but the physiological basis of this selective IFN response is not well understood. Here, we confirm that type III IFN treatment elicits robust and uniform ISG expression in neonatal mouse IECs and inhibits the replication of IEC-tropic rotavirus. In contrast, type I IFN elicits a marginal ISG response in neonatal mouse IECs and does not inhibit rotavirus replication. In vitro treatment of IEC organoids with type III IFN results in ISG expression that mirrors the in vivo type III IFN response. However, IEC organoids have increased expression of the type I IFN receptor relative to neonate IECs, and the response of IEC organoids to type I IFN is strikingly increased in magnitude and scope relative to type III IFN. The expanded type I IFN-specific response includes proapoptotic genes and potentiates toxicity triggered by tumor necrosis factor alpha (TNF-α). The ISGs stimulated in common by type I and III IFNs have strong interferon-stimulated response element (ISRE) promoter motifs, whereas the expanded set of type I IFN-specific ISGs, including proapoptotic genes, have weak ISRE motifs. Thus, the preferential responsiveness of IECs to type III IFN in vivo enables selective ISG expression during infection that confers antiviral protection but minimizes disruption of intestinal homeostasis.IMPORTANCE Enteric viral infections are a major cause of gastroenteritis worldwide and have the potential to trigger or exacerbate intestinal inflammatory diseases. Prior studies have identified specialized innate immune responses that are active in the intestinal epithelium following viral infection, but our understanding of the benefits of such an epithelium-specific response is incomplete. Here, we show that the intestinal epithelial antiviral response is programmed to enable protection while minimizing epithelial cytotoxicity that can often accompany an inflammatory response. Our findings offer new insight into the benefits of a tailored innate immune response at the intestinal barrier and suggest how dysregulation of this response could promote inflammatory disease.

Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).

The role of interferon-γ in cardiovascular disease: an update.

Cardiovascular disease (CVD) is the leading cause of death, globally, and its prevalence is only expected to rise due to the increasing incidence of co-morbidities such as obesity and diabetes. Medical treatment of CVD is directed primarily at slowing or reversing the underlying atherosclerotic process by managing circulating lipids with an emphasis on control of low-density lipoprotein (LDL) cholesterol. However, over the past several decades, there has been increasing recognition that chronic inflammation and immune system activation are important contributors to atherosclerosis. This shift in focus has led to the elucidation of the complex interplay between cholesterol and cellular secretion of cytokines involved in CVD pathogenesis. Of the vast array of cytokine promoting atherosclerosis, interferon (IFN)-γ is highly implicated and, therefore, of great interest. Literature review was performed to further understand the effect of IFN-γ on the development of atherosclerotic CVD. IFN-γ, the sole member of the type II IFN family, is produced by T cells and macrophages, and has been found to induce production of other cytokines and to have multiple effects on all stages of atherogenesis. IFN-γ activates a variety of signaling pathways, most commonly the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, to induce oxidative stress, promote foam cell accumulation, stimulate smooth muscle cell proliferation and migration into the arterial intima, enhance platelet-derived growth factor expression, and destabilize plaque. These are just a few of the contributions of IFN-γ to the initiation and progression of atherosclerotic CVD. Given the pivotal role of IFN-γ in the advancement of CVD, activation of its signaling pathways is being explored as a driver of atherosclerosis. Manipulation of this key cytokine may lead to novel therapeutic avenues for CVD prevention and treatment. A number of therapies are being explored with IFN-γ as the potential target.

The role of IL-29 in obesity-induced inflammation and insulin resistance

Abstract Adipocyte-macrophage crosstalk plays a critical role in regulating adipose tissue microenvironment and causes chronic inflammation in the pathogenesis of obesity. Interleukin-29 (IL-29), a member of type 3 interferon family, plays a role in host defenses against microbes. The macrophage is one of the cellular sources of IL-29; however, the role of IL-29 in metabolic disorders is still unclear. We explored the function of IL-29 in the pathogenesis of obesity-induced inflammation and insulin resistance. We found that serum IL-29 level was significantly higher in obese patients. IL-29 upregulated IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) expression and decreased glucose uptake and insulin sensitivity in human SGBS adipocytes through reducing glucose transporter 4 (GLUT4) and AKT signals. Inhibition of IL-29 could reduce inflammatory cytokine production in the macrophage-adipocyte co-culture system, which mimics an obese microenvironment. In vivo, IL-29 reduced insulin sensitivity and increased the number of peritoneal macrophages in high-fat diet (HFD)-induced obese mice. IL-29 increased M1/M2 macrophage ratio and enhanced MCP-1 expression in adipose tissues of HFD mice. Therefore, we have identified a critical role of IL-29 in obesity-induced inflammation and insulin resistance, and we conclude that IL-29 may be a novel candidate target for inhibiting obesity-induced inflammation and insulin resistance in patients with metabolic disorders.

Development and biological activity of long-acting recombinant human interferon-\u03b12b

BackgroundThe type I human interferon (IFN) family consists of a group of cytokines with a multiplicity of biological activities, including antiviral, antitumor, and immunomodulatory effects. However, because the half-life of IFN is short, its clinical application is limited. Increasing the yield and biological activity of IFN while extending its half-life is currently the focus of IFN research.ResultsTwo novel long-acting recombinant human IFN-α2b (rhIFN-α2b) proteins were designed in which the carboxyl-terminal peptide (CTP) of the human chorionic gonadotropin β su bunit and N-linked glycosylation sequences were linked to rhIFN-α2b. They were designated IFN-1CTPON (fused at the C-terminus of rhIFN-α2b) and IFN-2CTPON (fused at both the C-terminus and N-terminus of rhIFN-α2b). Monoclonal CHO cell strains stably and efficiently expressing the IFNs were successfully selected with methotrexate (MTX), and the highest expression levels were 1468 mg/l and 1196 mg/l for IFN-1CTPON and IFN-2CTPON, respectively. The proteins were purified with affinity chromatography and molecular sieve chromatography. IFN-1CTPON and IFN-2CTPON showed antiviral and antiproliferative activities in vitro. Notably, the half-life of IFN-1CTPON and IFN-2CTPON in vivo were three-fold and two-fold longer than that of commercially available rhIFN-α2b.ConclusionsCHO cell strains stably expressing long-acting rhIFN-α2b were screened. The purified IFN-CTPON protein has biological activity and an extended half-life, and therefore potential applications.

Mathematical Modeling for Hepatitis B Virus: Would Spatial Effects Play a Role and How to Model It?

For nearly 250 million people worldwide suffering from chronic hepatitis B virus (HBV) infection, there are few effective options for treatment (Schweitzer et al., 2015). Elimination of HBV from liver tissue remains an elusive goal; chronic HBV is exceptionally difficult to treat. It results mainly from maternal-neonatal vertical infection but also in roughly 5% of horizontal infections (Rehermann, 2013), and is characterized by the entrenchment of viral covalently closed circular DNA (cccDNA) in host nuclei. cccDNA persistence and HBV resurgence under multiple scenarios [e.g., immunosuppression for chemotherapy (Hoofnagle, 2009)] are associated with liver pathologies such as tissue damage (fibrosis, cirrhosis) and hepatic carcinomas (Ikeda et al., 2010). Current treatments are aimed at mitigating such long-term pathological effects and require sustained and prolonged protocols, yet do not eradicate cccDNA leading to reactivation upon cessation (Guo and Guo, 2015). cccDNA entrenchment further evades detection—with some occult DNA levels well under 100 copies/ml—complicating transfusions or transplantations (Schmeltzer and Sherman, 2010). Efforts at mimicking and exploiting the successful immune response in the 95% of acute horizontal infections requires delineating precisely how the immune systems interact with HBV, and we do not have a clear characterization of the HBV-immune dynamic (Guidotti et al., 2015; Seeger and Mason, 2015). The two levels of infectious response, (i) the innate and (ii) the adaptive, recognize and respond in distinct ways to HBV challenges while modulating each other. Their success or failure influences whether the HBV challenges are resolved with an acute infection and immunity, or a chronic condition with numerous collateral complications (Rehermann, 2013). Innate immune activity, as with the natural killer (NK) cells and resident liver macrophages, or the Kupffer cells, and its more generalized recognition of pathogens are proposed either essentially blind to a “stealth” infection of HBV (Chang and Guo, 2015), or are a critical and “exquisite” guardian against successful HBV colonization (Guidotti et al., 2015). Meanwhile, adaptive responses (e.g., CD4+/CD8+ T-Cells) and their specific targeting of HBV are proposed essential for restricting infection to the transient acute while buttressing immunity against future challenges (Chisari et al., 2010). Evaluating novel treatments is further complicated by observations of evidently disruptive interactions between innate and adaptive immune activity. Uptake mechanisms observed key to HBV invasion, the sodium-taurocholate co-transporting polypeptide or NTCP (Watashi et al., 2014), is a promising target for blocking HBV uptake. However, innate release of interleukin-6 (IL-6) that interferes with HBV replication and downregulates NTCP also blocks apoptotic mechanisms and may even assist HBV progress (Hosel et al., 2009). The HBV cccDNA itself is a natural prime target, and in vitro studies with HepaRG cell lines that show interferon-alpha and lymphotoxin-beta stimulus without cytolytic behavior appears promising (Lucifora et al., 2014), but must be advanced with caution. Innate NK cells were observed to perform unexpected termination of adaptive CD8+ T-cells when pharmacologically stimulated to produce interferon family cytokines (Guidotti et al., 2015). Additionally, dependence of chronic or acute manifestations on the sheer number of HBV suggests an optimal invasion population strategy for HBV (Asabe et al., 2009), presumably evading detection but sufficient for colonization. Unfortunately, direct study of the initial HBV-immune dynamic in patients is difficult or simply not possible, hence the attention given to animal and mathematical models (Murray and Goyal, 2015; Cangelosi et al., 2017).