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Atypical porcine pestivirus (APPV) is an emerging porcine virus that threatens global swine production. Pestiviruses can prevent interferon (IFN) production to avoid the host innate immune response, and the Npro viral protein can play a critical role. Knowledge of the host immune response to APPV infection is limited. Here, we showed that the IFN-β production was suppressed by APPV-Npro and the IFN regulatory factor 3 (IRF3) promoter activity stimulated by adaptor molecules of the IFN-β signaling pathway was also inhibited in the APPV-Npro-expressed cells. The APPV-Npro was able to interact with IRF3 and interfere the phosphorylation of IRF3, indicated that the IFN-β antagonism of APPV-Npro mainly depended on blocking IRF3 activity. To identify the functional region of APPV-Npro, a panel of truncated APPV-Npro was constructed, and its influence on the IRF3 activation was investigated. The results showed that the N-terminal 31–51 amino acids of APPV-Npro were mainly associated with inhibition of the IFN-β response. Taken together, this is the first study focusing on elucidating the function of APPV protein by revealing a novel mechanism of Npro in disruption of host IFN-β production, which will enlighten future study in addressing APPV pathogenesis and immune evasion.

Several predictors of non-response to interferon-β (IFN-β) treatment have been proposed. The aim of the study was to identify metabolite changes in the normal-appearing cortex of the posterior cingulate gyrus (PCG) using MRS (magnetic resonance spectroscopy) and to investigate their usefulness in prognosis of NEDA (no evidence of disease activity) in the 3-year follow-up and in monitoring treatment effects during IFN-β therapy in the parallel period of time in multiple sclerosis (MS) patients. Forty-one relapsing-remitting MS patients and 41 sex- and age-matched healthy subjects underwent routine MRI protocol with MRS sequence with the use of a 1.5 T magnet. A single voxel size of 2x2x2cm was inserted in the cortex of PCG region. Associations between baseline metabolic ratios, conventional MRI findings, demographic and clinical factors, and NEDA status were evaluated using logistic, Cox, and multinomial logistic regression models. MS patients in the initial scan showed a statistically significant decline in NAA/Cr ratio (p 0.0001) and an increase in Cho/Cr ratio (p = 0.016) compared to the control group. None of the MRS parameters predicted NEDA maintenance or the time to loss of NEDA. In treatment monitoring only an improvement in the combination of NAA/Cr + Cho/Cr ratio between the 1st and 2nd year of treatment was connected with a 6.27-fold chance (p = 0.025) of having simultaneous NEDA maintenance. To conclude, metabolite alterations in the PCG region did not predict NEDA maintenance, but they seem to be useful in treatment monitoring.

Background In systemic lupus erythematosus (SLE), detection of interferon-β (IFNβ) in B cells was found to be most prominent in patients with high anti-Smith (Sm) and renal disease, but a mechanistic connection was not clear. The objective of the present study is to determine the association of IFNβ in peripheral blood naïve B cells with the histopathological features of lupus nephritis (LN). Methods The percentage of IFNβ+ cells in IgD+CD27− naïve CD19+ B cells (B cell IFNβ) among peripheral blood mononuclear cells (PBMCs) from 80 SLE patients were analyzed using flow cytometry. Serological and clinical data were collected. The correlations of B cell IFNβ with LN classification and with histopathological findings (light, electron, and immunofluorescence [IF] microscopic analyses for deposition of IgM, IgG, IgA, C1q, and C3) were determined in 23 available biopsy specimens. Results B cell IFNβ is positively associated with anti-Sm (p = 0.001), anti-DNA (p = 0.013), and LN (p < 0.001) but was negatively associated with oral/nasal ulcer (p = 0.003) and photosensitivity (p = 0.045). B cell IFNβ positively correlated with immune complex (IC) deposit in the glomerular basement membrane (GBM) (p = 0.002) but not in the mesangial (p = 0.107) or tubular region (p = 0.313). Patients with high B cell IFNβ had statistically increased development of the proliferative LN (Classes III, IV and/or V), compared to patients with low B cell IFNβ (p p = 0.023), chronic glomerular lesions indicated by segmental sclerosis (p = 0.033), and a membranous pattern of renal damage indicated by spike/holes (p = 0.015). Conclusion B cell IFNβ correlates with history of severe LN, glomerular basement membrane (GBM) IC deposition, and anatomical features of both active and chronic glomerular lesions.

Interferon (IFN)-β has been classified as a drug that is possibly associated with development of pulmonary arterial hypertension (PAH), a devastating disease that can lead to right heart failure and premature death [1]., The possible causal relationship between interferon-β exposure and pulmonary arterial hypertension development requires close follow-up of patients on treatment with interferon-β http://bit.ly/2OPGSVP

Highlights • TRIM25, a novel host factor, inhibits replication of PRRSV. • PRRSV N protein impedes TRIM25–RIG-I interactions by competitively binding TRIM25. • PRRSV N inhibits TRIM25 expression and RIG-I ubiquitination to suppress IFN-β production. • TRIM25 diminishes the inhibitory effect of PRRSV N on RIG-I ubiquitination., Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), and is characterized by respiratory diseases in piglet and reproductive disorders in sow. Identification of sustainable and effective measures to mitigate PRRSV transmission is a pressing problem. The nucleocapsid (N) protein of PRRSV plays a crucial role in inhibiting host innate immunity during PRRSV infection. In the current study, a new host-restricted factor, tripartite motif protein 25 (TRIM25), was identified as an inhibitor of PRRSV replication. Co-immunoprecipitation assay indicated that the PRRSV N protein interferes with TRIM25–RIG-I interactions by competitively interacting with TRIM25. Furthermore, N protein inhibits the expression of TRIM25 and TRIM25-mediated RIG-I ubiquitination to suppress interferon β production. Furthermore, with increasing TRIM25 expression, the inhibitory effect of N protein on the ubiquitination of RIG-I diminished. These results indicate for the first time that TRIM25 inhibits PRRSV replication and that the N protein antagonizes the antiviral activity by interfering with TRIM25-mediated RIG-I ubiquitination. This not only provides a theoretical basis for the development of drugs to control PRRSV replication, but also better explains the mechanism through which the PRRSV N protein inhibits innate immune responses of the host.

Objective: To evaluate the value of combined interferon β (IFN-β) and platelet (PLT) detection for Kawasaki disease (KD) identification.Methods: Forty-four children who were newly diagnosed with KD were selected as the KD group. They were divided into acute phase of KD and subacute phase of KD. They were also separated into groups with and without coronary artery disease (CAD) (CAD+ and CAD–, respectively). Meanwhile, 44 children hospitalized with febrile disease and 44 healthy children were selected as a febrile control group and normal control group, whom were attended to at Children's Hospital of Soochow University at the same time. We detected the concentration of IFN-β and PLT of peripheral blood serum for all three groups and analyzed the difference.Results: At acute and subacute phases of KD, both IFN-β and PLT are higher than both the febrile control group and healthy control group, especially at subacute phase; the difference between groups was statistically significant, P < 0.05. Receiver operating characteristic (ROC) curve showed that the areas under the ROC curve (AUCs) of IFN-β and PLT at acute phase of KD were 0.81 and 0.72, respectively; the sensitivity and specificity were 97.22 and 63.64%, and 57.89 and 73.86%, respectively. The AUCs of combined IFN-β and PLT were 0.81 at acute phase and 0.96 at subacute phase of KD, with sensitivity and specificity of 97.22 and 55.26%, and 86.36 and 100%, respectively. The cutoff value of combined IFN-β and PLT detection was IFN-β = 3.51 pg/ml and PLT = 303 × 109/L at acute phase of KD, IFN-β = 4.21 pg/ml and PLT = 368 × 109/L at subacute phase from plot vs. criterion values. However, there are no significant differences between the CAD– group and the CAD+ group for combined IFN-β and PLT, both P > 0.5, neither at acute nor at subacute phase of KD.Conclusion: Combined IFN-β and PLT detection is an efficient biomarker for KD identification. The cutoff values are IFN-β = 3.51 pg/ml and PLT = 303 × 109/L at acute phase of KD and IFN-β = 4.21 pg/ml and PLT = 368 × 109/L at subacute phase.

Background: Multiple Sclerosis (MS) is one of the most common causes of neurological disability in young and middle-aged adults. Patients with MS face many challenges, both physical and emotional, and see an overall reduction in their autonomy. There is no definitive treatment for MS, though Disease Modifying Drugs (DMDs) have proved effective in reducing the frequency and severity of relapses. Unfortunately, long-term adherence to these therapies is a significant challenge due to practical difficulties as well as a general distrust towards the drugs . Objective: This study follows an original research carried out in 2008. In the first study, patients answered questions on their clinical history and expressed their judgment on the pharmacological treatment, their perceived effectiveness and factors that may undermine compliance. They have been recalled after two years to verify if the reported symptoms have changed and to assess how their knowledge of the disease and “acceptance” of the treatment have been modified. Methods: In spite of the relatively high number of patients participating in the first study (141 patients followed at a single neurological centre), only 16 patients have completed the questionnaire for the long-term survey. A detailed descriptive analysis has been carried out, as well as a pairwise correlation analysis. Results and Conclusions: The interviews carried out gave an insight into how patients’ behavior may have changed over time. Compliance rate is different in newly-diagnosed patients and long-term patients; the latter are more likely to be compliant, given their personal experience with the disease. Communications with neurologists and health personnel should aim at forming therapeutic alliances with patients and detecting their preferences for a qualitatively adequate assistance throughout their illness.

[Background] Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients., [Objectives] To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role. [Methods] Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNβ and TTFR. [Results] Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10−4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood (p = 7.0 × 10−6), which was confirmed in vitro (p = 0.009). Finally, NINJ2 expression is downregulated by IFNβ treatment and related to TTFR. [Conclusions] Rs7298096 could influence MS disease activity during IFNβ treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.

Interferon β (IFN-β) is considered a signaling molecule with important therapeutic potential in cancer since IFN-β-induced gene transcription mediates antiproliferation and cell death induction. Whereas, TNF-related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) has emerged as a promising anticancer agent because it induces apoptosis specifically in cancer cells. In this study, we elucidated that IFN-β augments TRAIL-induced apoptosis synergistically using five human malignant melanoma cells. All of these cells were induced apoptosis by TRAIL. Whereas, the response against IFN-β was different in amelanotic cells (A375 and CRL1579) and melanotic cells (G361, SK-MEL-28, and MeWo). The responsibility of amelanotic cells against IFN-β was higher than those of melanotic cells. The synergism of IFN-β and TRAIL were correlated with the responsibilities of the cells against IFN-β. The synergistic interaction was confirmed by a combination index based on the Chou-Talalay method. The upregulation of apoptosis in amelanotic cells was caused by very low doses of IFN-β (over 0.1 IU/ml). Both of p53-mediated intrinsic pathway and Fas-related extrinsic pathway were activated by IFN-β alone and combination with TRAIL. Further, TRAIL death receptors (DR4 and DR5) were upregulated by a low-dose IFN-β (over 0.1 IU/ml) and the expression was more promoted by the combination with TRAIL. It was clarified that the upregulation of DR5 is associated with the declination of viability.

Background Multiple sclerosis (MS) as a chronic autoimmune demyelinating disorder of the central nervous system has been associated with numerous genetic and environmental factors among them are functional variants within the angiotensin I converting enzyme (ACE) gene. Methods In the present study, we genotyped the rs4359 (C/T) and rs1799752 (Insertion (I)/Deletion (D)) of this gene in 391 MS patients and 380 age- and sex-matched controls. Results We found significant overrepresentation of the I allele of the rs1799752 in MS patients compared with healthy subjects (Adjusted P value = 0.03, OR (95% CI) = 1.28 (1.05–1.57). The same allele was associated with MS risk in co-dominant and dominant models (Adjusted P values of 0.007 and 0.002 respectively). The allele and genotype frequencies of the rs4359 were not significantly different between cases and controls. Moreover, the I allele of the rs1799752 was significantly overrepresented in MS patients who were irresponsive to IFN-β compared with healthy subjects (Adjusted P value = 0.04, OR (95% CI) = 1.57 (1.08–2.29)). The same allele was associated with irresponsiveness to IFN-β in dominant model (Adjusted P value = 0.02, OR (95% CI) = 2.32 (1.22–4.42)). Conclusion The present study provides further evidences for the role of ACE in MS risk or response of patients to IFN-β treatment.

Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US‐FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon‐beta (IFN‐β), an endogenous cytokine and a key anti‐inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN‐β may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN‐β along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN‐β therapy that may be helpful in improving stroke outcome are also discussed.

Background Interferon-β has been approved for the treatment of relapsing-remitting (RR) multiple sclerosis (MS), whereas its efficacy in preventing long-term disability and conversion to secondary progressive (SP) MS is still debated. We aim to compare long-term clinical evolution of newly-diagnosed RRMS patients treated with different Interferon-β formulations. Methods 507 patients were included in the analysis and followed-up for 8.5 ± 3.9 years. 37.6% were treated with subcutaneous Interferon-β1a 44mcg, 33.4% with intramuscular Interferon-β1a 30mcg, and 29.0% with subcutaneous Interferon-β1b 250mcg. Relapse occurrence, 1-point EDSS progression, reaching of EDSS 4.0 and conversion to SP were recorded as outcome measures. To reduce the selection bias, we calculated the propensity score of receiving the specific treatment considering age (32.7 ± 8.3 years), gender (female 63.1%), disease duration (2.7 ± 2.8 years), and baseline EDSS (1.5, range 1.0–3.5). Propensity score and covariates (age, gender, disease duration and EDSS) were included in the statistical models. Results At Cox regression models, the reaching of EDSS 4.0 was not-significantly higher for Interferon-β1b 250mcg (HR = 1.207; p=0.063) and for Interferon-β1a 30mcg (HR = 1.363; p=0.095), when compared with Interferon-β1a 44mcg. The rate of SP conversion was higher for Interferon-β1b 250mcg (HR = 2.054; p=0.042), and not-significantly higher for Interferon-β1a 30mcg (HR = 1.884; p=0.081), when compared with Interferon-β1a 44mcg. Conclusions Patients treated with Interferon-β1a 44mcg presented with a marginally reduced risk of disability accrual in the long-term, when compared with Interferon-β1b 250mcg and, at least in part, with Interferon-β1a 30mcg. Formulation, frequency of administration and dose of Interferon-β might affect the long-term clinical evolution of RRMS.

Porcine activating Fc gamma receptors (FcγRI and FcγRIII) have been cloned and characterized for many years. However, their roles in interferon (IFN) antiviral immune response to porcine reproductive and respiratory syndrome virus (PRRSV) infection have not yet been investigated extensively. In this study, PRRSV infection assay showed that PRRSV increased significantly the transcription of IFN-β, IFN-γ and IFN-λ1 in porcine alveolar macrophages (PAMs) in early infection and decreased significantly the transcription of IFN-β, IFN-γ and IFN-λ1 in PAMs in late infection. Activation assay showed that specific activation of FcγRI or FcγRIII in PAMs decreased significantly the transcription of IFN-β, IFN-γ and IFN-λ1 and increased significantly the transcription of transforming growth factor β1 (TGF-β1). PRRSV infection assay mediated by FcγRI and FcγRIII showed that specific activation of FcγRI or FcγRIII in PAMs during PRRSV infection decreased significantly the transcription of IFN-β, IFN-γ and IFN-λ1, but increased significantly the transcription of TGF-β1 and enhanced significantly viral replication. In conclusion, our studies suggested that activating FcγR signaling inhibited the transcriptional levels of IFN-β, IFN-γ and IFN-λ1 in PAMs in response to PRRSV infection.

Background We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients. Methods Comprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs). Results The percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = − 0.369, p = 0.005), and the percentages of Vδ1−Vδ2−Vγ9− cells in Vδ1−Vδ2− γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = − 0.976, p < 0.001). Conclusions The present study suggests that long-term usage of IFN-β increases Vδ1−Vδ2−Vγ9− γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1−Vδ2−Vγ9− cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.

Previous studies have demonstrated little efficacy of interferons (IFNs) in animal models of Ebola virus disease. However, these studies were limited to a small number of type I IFNs and, during the most recent outbreak of Ebola virus, questions regarding the suitability of the animal models to evaluate IFNs were raised. To address the potential that anti-Ebola virus activity was overlooked, type I and type II IFNs (α-2a, α-2b, -β, -γ, and -universal) were tested in a variety of cell types (Vero E6, Huh 7 cells, and human macrophages). IFNs are weak inhibitors of Ebola virus Makona in these cell lines.

Objective: To investigate the association between activity during interferon-beta (IFNβ) therapy and disability outcomes in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: A longitudinal study based on two previously described cohorts of IFNβ-treated RRMS patients was conducted. Patients were classified according to clinical activity after 2 years (clinical cohort) or to clinical and radiological activity after 1 year (magnetic resonance imaging (MRI) cohort). Multivariate Cox models were calculated for early disease activity predicting long-term disability. Results: A total of 516 patients from two different cohorts were included in the analyses. Persistent clinical disease activity during the first 2 years of therapy predicted severe long-term disability (clinical cohort). In the MRI cohort, modified Rio score and no or minimal evidence of disease activity (NEDA/MEDA) did not identify patients with risk of Expanded Disability Status Scale (EDSS) worsening. However, a Rio score ≥ 2 (hazard ratio (HR): 3.3, 95% confidence interval (CI): 1.7–6.4); ≥3 new T2 lesions (HR: 2.9, 95% CI: 1.5–5.6); or ≥2 Gd-enhancing lesions (HR: 2.1, 95% CI: 1.1–4) were able to identify patients with EDSS worsening. Conclusion: Although early activity during IFNβ therapy is associated with poor long-term outcomes, minimal degree of activity does not seem to be predictive of EDSS worsening over 6.7-year mean follow-up.

The hemolytic uremic syndrome (HUS) is one of the thrombotic microangiopathies and it consists of the triad of nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The atypical form of HUS (aHUS) is related to causative mutations in complement genes. Some conditions act as a trigger for aHUS in individuals that have a genetic background predisposing to complement activation. Interferon β is a recombinant-protein therapy approved to treat multiple sclerosis (MS), and can be a causative agent in the occurrence of HUS through anti-angiogenic activity. In this paper, we briefly review aHUS clinical and genetic characteristics. Furthermore, we present a case of a 48-year-old woman, diagnosed with MS and treated with INFβ-1b from 2008. In December 2015, she presented with asthenia and loss of muscular strength in the legs and she quickly developed aHUS. Our case suggests that INFβ is a possible triggering factor for HUS.

Gene therapy techniques aiming to induce the long-term interferon-β (IFN-β) expression are desirable for inhibiting cancer growth. However, there has been no success in this regard because IFN-β significantly inhibits transgene expression. This study used the IFN-inducible Mx promoter to promote IFN-β expression. The pMx-IFN-β plasmid was constructed to achieve long-term IFN-β expression. In cultured cells transfected with the Mx promoter-driven reporter protein plasmid, IFN-β induced concentration-dependent expression of the reporter protein. After the hydrodynamic injection of pMx-IFN-β into mice, the serum concentration of IFN-β was maintained at ≥100 pg/mL for1 month. IFN-β expression was significantly suppressed by the co-injection of small interfering RNA targeting the interferon-α/β receptor (IFNAR), suggesting that IFN-β binding to IFNAR increased IFN-β expression. Moreover, the hydrodynamic injection of pMx-IFN-β significantly suppressed the growth of colon26 tumors in mice. In contrast, a conventional promoter-driven plasmid was less effective than pMx-IFN-β in all the experiments. Taken together, these results indicate that the interferon-inducible Mx promoter-driven expression system effectively achieves long-term expression of IFN-β and represents a potential tool for cancer gene therapy.

Temozolomide (TMZ) is an oral alkylating agent used to treat glioblastoma multiforme (GBM) and astrocytomas. However, at least 50% of TMZ treated patients do not respond to TMZ. This is due primarily to the over-expression of O6-methylguanine methyltransferase (MGMT) and/or lack of a DNA repair pathway in GBM cells. Multiple GBM cell lines are known to contain TMZ resistant cells and several acquired TMZ resistant GBM cell lines have been developed for use in experiments designed to define the mechanism of TMZ resistance and the testing of potential therapeutics. However, the characteristics of intrinsic and adaptive TMZ resistant GBM cells have not been systemically compared. This article reviews the characteristics and mechanisms of TMZ resistance in natural and adapted TMZ resistant GBM cell lines. It also summarizes potential treatment options for TMZ resistant GBMs.

Mycobacteria other than Mycobacterium tuberculosis complex and M. leprosy are collectively known as Non-tuberculous Mycobacteria (NTM). NTM are a diverse family of environmental acid-fast bacteria ...

Tumor vasculature plays a central role in tumor progression, making it an attractive therapeutic target. In this study, we explore the antiangiogenic potential of our melanoma gene therapy approach combining interferon β (IFNβ) and p19Arf gene transfer. Since these proteins are modulators of tumor vasculature, we explore the impact of IFNβ and p19Arf gene transfer on murine endothelial cells (tEnd). Adenovirus-mediated gene transfer of p19Arf to tEnd cells inhibited proliferation, tube formation, migration, and led to increased expression of genes related to the p53 cell death pathway, yet IFNβ gene transfer had no significant impact on tEnd viability. Alternatively, tEnd cells were exposed to the factors generated by transduced B16 (mouse melanoma) cells using either coculture or conditioned medium. In either case, transduction of B16 cells with the IFNβ vector, whether alone or in combination with p19Arf, resulted in endothelial cell death. Strikingly, treatment of tEnd cells with recombinant IFNβ did not induce death, demonstrating that additional factors produced by B16 cells contributed to the demise of tEnd cells. In this work, we have shown that our melanoma gene therapy strategy produces desirable negative effects on endothelial cells, possibly correlating with antiangiogenic activity.

IntroductionInterferon (IFN)-β is known as an environmental trigger for the occurrence of autoimmune thyroid disease (AITD). However, the association of another type-1 IFN, IFN-β, with AITD is unknown.Material and methodsIn the study, we explored the association of serum IFN-β levels with AITD in an ethnic Chinese (i.e., Taiwanese) population. We enrolled 160 patients with Graves’ disease (GD), 47 patients with Hashimoto’s thyroiditis (HT), and 119 healthy controls. Serum IFN-β and B-cell activating factor (BAFF) levels were quantified in healthy controls at the baseline and in patients with AITD either prior to receiving medication or while under medication. Thyroid function and thyroid-stimulating hormone receptor antibody (TSHRAb) levels were measured at the time of serum collection.ResultsSerum IFN-β levels were lower in the HT group than in the control group (p = 0.031). A significant inverse correlation was observed between IFN-β and TSHRAb levels in men with GD (r = –0.433, p = 0.044). Serum IFN-β levels were also negatively associated with BAFF levels in men with GD, HT, and AITD (r = –0.320, p = 0.032; r = –0.817, p = 0.047; and r = –0.354, p = 0.011, respectively), but not in women with GD, HT, or AITD.ConclusionsSerum IFN-β levels were lower in HT patients. Correlations of serum IFN-β with TSHRAb and BAFF levels were found to be gender-specific. Further well-designed studies with larger sample sizes are required to confirm our findings.

Drug-Induced Pulmonary Arterial Hypertension (PAH) represents a well-known entity, predominantly related to anorexigens. Interferon-β (IFN) is considered to be a drug with a possible risk of inducing PAH. We report a patient with Multiple Sclerosis treated with IFN-β who diagnosed with PAH and her course of disease under specific PAH drug therapy. A review of the literature in IFN-β-induced PAH is provided.

Increased expression of cytosolic DNA sensors, a category of pattern recognition receptor, after control plasmid DNA electrotransfer was observed in our previous studies on B16.F10 murine melanoma cells. This expression was correlated with the upregulation of proinflammatory cytokines and chemokines and was associated with cell death. Here, we expanded our research to include the influence of features of cells in a 3-dimensional environment, which better represents the tumors' organization in vivo. Our results show that lower number of cells were transfected in spheroids compared to 2-dimensional cultures, that growth was delayed after electroporation alone or after electrotransfer of plasmid DNA, and that DNA sensors DDX60, DAI/ZBP1, and p204 were upregulated 4 hours and 24 hours after electrotransfer of plasmid DNA. Moreover, the cytokines interferon β and tumor necrosis factor α were also upregulated but only 4 hours after electrotransfer of plasmid DNA. Thus, our results confirm the results obtained in 2-dimensional cell cultures demonstrating that electrotransfer of plasmid DNA to tumor cells in spheroids also upregulated cytosolic DNA sensors and cytokines.

Therapies - In Press.Proof corrected by the author Available online since lundi 21 janvier 2019

A series of controlled clinical trials have shown that exogenous interferon-beta (IFN-β) benefits patients with relapsing–remitting multiple sclerosis (RRMS) by reducing relapse rate, disability progression, and the formation of new brain and spinal cord lesions on magnetic resonance imaging (MRI) scans. Unfortunately, however, the effectiveness of IFN-β is limited in this setting by the occurrence of treatment non-responsiveness in nearly 25% of patients. Furthermore, clinicians who care for RRMS patients remain unable to accurately identify IFN-β non-responders prior to the initiation of therapy, causing delays in the use of alternative treatments and sometimes requiring that patients turn to medications with more significant side effects to control their disease. Progress has been made toward understanding how both endogenous and exogenous IFN-β act to slow RRMS as well as the related mouse model, experimental autoimmune encephalomyelitis (EAE). Most studies point to its inhibitory actions on circulating immune cells as being important for suppressing both disorders, but multiple potential target cells and inflammatory pathways have been implicated and those essential to confer its benefits remain undefined. This review focuses on the role of both endogenous and exogenous IFN-β in RRMS, paying particular attention to the issue of why certain individuals appear refractory to its disease-modifying effects. A continued goal in this field remains the identification of a convenient biomarker that accurately predicts IFN-β treatment non-responsiveness in individual RRMS patients. Development of such an assay will allow clinicians to customize therapy for patients with this complex disorder.

Nucleus accumbens-associated protein 1 (NAC1), a transcriptional co-regulator, is overexpressed in advanced prostate cancer. However, the NAC1-regulated transcriptome has not been completely explored. In the present study, the functional silencing of NAC1 blocked the migration of prostate cancer cells and suppress osteoclastogenesis. The present study also determined that NAC1 was overexpressed in the highly aggressive prostate cancer cell lines PC-3, DU-145 and LNCaP. NAC1 small interfering RNA treatment of DU-145 cells decreased cell migration, but interestingly had no significant effects on cell proliferation. Furthermore, microarray analysis showed that a group of genes may be associated with the development of prostate cancer after NAC1 knockdown, including interferon-β (IFNβ), which is reported to be involved in osteoclastogenesis, an important factor affecting bone metastasis. The mechanisms of NAC1 function were further explored by co-culture studies using PC-3 and RAW264.7 osteoclast precursor cells, which demonstrated that silencing NAC1 downregulated the genes associated with the activation of osteoclasts. Furthermore, it was revealed that NAC1 had the ability to affect the release of IFNβ into the extracellular environment. Together, these findings indicated that NAC1 promoted cell migration, and that NAC1 may have a key role in osteoclastogenesis.

Human type I interferons are a family of pleiotropic cytokines with antiviral, anti-proliferative and immunomodulatory activities. They signal through the same cell surface receptors IFNAR1 and IFNAR2 yet evoking markedly different physiological effects. One differentiating factor of interferon-beta (IFN-β) from other type I interferons is the presence of theAsn-Gly-Arg (NGR) sequence motif, which, upon deamidation, converts to Asp-Gly-Arg (DGR) and iso-Asp-Gly-Arg (iso-DGR) motifs. In other proteins, the NGR and iso-DGR motifs are reported as CD13- and αvβ3, αvβ5, αvβ6, αvβ8 and α5β1 integrin-binding motifs, respectively. The scope of this study was to perform exploratory surface plasmon resonance (SPR) experiments to assess the binding properties of a deamidated IFN-β variant to integrins. For this purpose, integrin αvβ3 was selected as a reference model within the iso-DGR- integrin binding members. The obtained results show that deamidated IFN-β binds integrin αvβ3 with nanomolar affinity and that the response was dependent on the deamidation extent. Based on these results, it can be expected that deamidated IFN-β also binds to other integrin family members that are able to bind to the iso-DGR binding motif. The novel binding properties could help elucidate specific IFN-β attributes that under physiological conditions may be modulated by the deamidation.

BACKGROUND We present a case of acute rhabdomyolysis in the setting of interferon-β treatment and concomitant pomelo juice ingestion, with concern of possible pharmacological interaction, which has not yet been described in the literature. CASE PRESENTATION A young Caucasian female with multiple sclerosis on chronic therapy with interferon-β presented with acute rhabdomyolysis after mild exercise and concomitant ingestion of pomelo extract. After stopping the suspected drugs, the signs of rhabdomyolysis diminished, the subsequent course was favorable. CONCLUSIONS The most probable cause of rhabdomyolysis in our patient could have been the combination of interferon effect, which down-regulates P450 expression, with inhibition of the P450 activity by furanocoumarin derivatives from pomelo juice. Therefore, patients treated with drugs that have a possible interaction with inhibitors of cytochrome P450 should be warned against pomelo ingestion. .

Background Peritendinous adhesion is the most common complication after tendon surgery, particularly in zone II of the hand. Prevention of inflammation around the tendon, which develops after trauma and surgery, can decrease the tendon adhesion formation. This study compares the effect of some anti-inflammatory cytokines with 5-fluorouracil (5-FU) on the tensile strength and in prevention of peritendinous adhesion formation. Methods Sixteen rabbits were allocated equally into 4 groups. Tendons of the index and ring fingers in zone II of the right hind paw were cut in all animals and then repaired. Interferon (IFN)-α in group 1, 5-FU in group 2, normal saline in group 3, and IFN-β in group 4 were locally applied to the repaired sites. Three weeks later, tensometric and histopathologic evaluations were performed. Results The force required for removing the tendon from the sheath was not different between the groups (P = 0.130), but the time required for removal was significantly shorter in 5-FU group (P = 0.049). The strength of repair was not different between the groups in terms of force and time needed for rupture (P = 0.11 and 0.67, respectively). In histopathologic examination, normal architecture of the tendon and peritendon environment was less disturbed in the IFN groups, especially in IFN-β specimens. Conclusions Local application of 5-FU significantly reduced peritendinous adhesion. Local IFN-α and IFN-β had no significant effect on the prevention of peritendinous adhesion formation. The strength of the repair was not affected by these cytokines and 5-FU.

Methylprednisolone (MP) has been recommended as a standard drug in MS therapies. We previously demonstrated that IFNβ-secreting human bone marrow-derived mesenchymal stem cells (MSCs-IFNβ) exert immunomodulatory effects in experimental autoimmune encephalomyelitic (EAE) mice. In this study, we evaluated whether a combined treatment of MP and MSCs-IFNβ had enhanced therapeutic effects on EAE mice. The combination treatment resulted in enhanced immunomodulatory effects, including reduced production of pro-inflammatory cytokines and increased production of anti-inflammatory cytokines. Thus, our results provide a framework for designing novel experimental protocols to enhance the therapeutic effects of existing MS treatments.

Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (ΔΨm) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls ( p < 0.001). Mitochondrial effects were reflected by depolarization of ΔΨm. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders ( p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.

The aim of this retrospective study was to preliminarily assess whether the EP-score, a summary score derived from multimodal evoked potentials tests, might be used as a measure of treatment efficacy in multiple sclerosis (MS).A sample of 56 relapsing remitting MS (RRMS) patients who at diagnosis started treatment with interferon β (INFβ, n = 19), glatiramer acetate (GA, n = 15) or refused any chronic treatment were assessed at baseline (before treatment) and at a median of 1.7 and 3.6 years thereafter. Outcome variables were Expanded Disability Status Scale (EDSS), EP-Score, visual evoked potentials (VEP) and somatosensory evoked potentials (SEP) scores measured as differences between baseline and follow-ups. Statistical differences between groups and follow-ups were assessed using non-parametric analyses.Treatment effects were not significant for EDSS both at the first and at the second follow-up, while a trend toward significance was observed in the EP-score only in the first follow-up (p = 0.07). Post-hoc analysis showed a greater decrease in median VEP-score for the IFNβ group compared to the GA and DF groups at both the first and second follow-ups.We found no evidence that either INFβ or GA significantly improved disability in RRMS patients. Using the EP-score as an outcome measure, we found that it was improved at both follow-ups in the INFβ group mainly due to a decrease in the VEP-score. This finding supports the proposal to include the EP-score as an additional outcome variable in future studies of treatment efficacy in MS.

Various diseases require the selection of preferable treatment out of available alternatives. Multiple sclerosis (MS), an autoimmune inflammatory/neurodegenerative disease of the CNS, requires long-term medication with either specific disease-modifying therapy (DMT) – IFN-β or glatiramer acetate (GA) – which remain the only first-line DMTs in all countries. A significant share of MS patients are resistant to treatment with one or the other DMT; therefore, the earliest choice of preferable DMT is of particular importance. A number of conventional pharmacogenetic studies performed up to the present day have identified the treatment-sensitive genetic biomarkers that might be specific for the particular drug; however, the suitable biomarkers for selection of one or another first-line DMT are remained to be found. Comparative pharmacogenetic analysis may allow the identification of the discriminative genetic biomarkers, which may be more informative for an a priori DMT choice than those found in conventional pharmacogenetic studies. The search for discriminative markers of preferable first-line DMT, which differ in carriage between IFN-β responders and GA responders as well as between IFN-β nonresponders and GA nonresponders, has been performed in 253 IFN-β-treated MS patients and 285 GA-treated MS patients. A bioinformatics algorithm for identification of composite biomarkers (allelic sets) was applied on a unified set of immune-response genes, which are relevant for IFN-β and/or GA modes of action, and identical clinical criteria of treatment response. We found the range of discriminative markers, which include polymorphic variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes, in different combinations. Every allelic set includes the CCR5 genetic variant, which probably suggests its crucial role in the modulation of the DMT response. Special attention should be given to the (CCR5*d+ IFNAR1*G) discriminative combination, which clearly points towards IFN-β treatment choice for carriers of this combination. As a whole the comparative approach provides an option for the identification of prognostic composite biomarkers for a preferable medication among available alternatives.

Schilder disease, also termed diffuse myelinoclastic sclerosis, is characterized by a large demyelinating lesion involving 1 or both sides of the centrum semiovale of the cerebral hemispheres. It often presents with tumorlike features and poses a diagnostic challenge. Schilder disease can be monophasic or relapsing, and disease-modifying therapy for the latter scenario is largely empirical. Here, we report a 14-year-old girl with relapsing Schilder disease within 1 year after disease onset. She has been followed-up for nearly 10 years and remains in sustained remission ever since interferon-β therapy was prescribed after the second attack. In this case study, it is suggested that interferon-β may induce long-term remission in relapsing Schilder disease and is therefore worth considering in this regard.

At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 5′ triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3′→5′ through the Ski-exosome complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5′ caps and destruction of faulty adducts in 5′→3′ fashion; and (d) STK19 on nuclear protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease.

RIG-I senses viral RNA in the cytosol and initiates host innate immune response by triggering the production of type 1 interferon. A recent RNAi knockdown screen yielded close to hundred host genes whose products affected viral RNA-induced IFN-β production and highlighted the complexity of the antiviral response. The stress granule protein G3BP1, known to arrest mRNA translation, was identified as a regulator of RIG-I-induced IFN-β production. How G3BP1 functions in RIG-I signaling is not known, however. Here, we overexpress G3BP1 with RIG-I in HEK293T cells and found that G3BP1 significantly enhances RIG-I-induced