Search

Viral infections in tubular epithelial cells lead to the production of inflammatory cytokines by innate immunity, causing tubulointerstitial nephritis. TLR3 recognizes viral infections and acts via the activation of interferon (IFN)/IFN‐stimulated genes (ISGs). This study investigates the role of ISG56, a representative ISG, in TLR3 signaling in cultured human renal proximal tubular epithelial cells (hRPTECs). To this end, hRPTECs were stimulated by a synthetic TLR3 ligand, polyinosinic‐polycytidylic acid (poly IC), recombinant human interferon‐β [r(h)IFN‐β] or Japanese encephalitis virus (JEV) infection and assayed for inflammatory cytokine mRNA expression by RT‐qPCR, and protein expression via western blotting or ELISA. ISG56 was expressed by poly IC or r(h)IFN‐β and IFN‐β knockdown reduced poly IC‐induced expression of ISG56 and CXCL10. Moreover, ISG56 knockdown reduced poly IC‐ or r(h)IFN‐β‐induced expression of CXCL10 at the same time as increasing JEV growth and reducing CXCL10 expression induced by JEV infection. Overall, TLR3 signaling induced IFN‐β‐dependent expression of ISG56 and CXCL10. We show that ISG56 possibly plays a critical role in antiviral immunity of hRPTECs by positive regulation of IFN‐β‐mediated CXCL10 expression downstream of TLR3. [ABSTRACT FROM AUTHOR]

Recently, members of the semaphorin family have received major attention in various medical fields, especially autoimmunity. In this study, we selected semaphorin-3A (Sema3A), semaphorin-7A (Sema7A), and their receptors to determine the possible relationship between these molecules and multiple sclerosis (MS). We measured the gene expression of Sema3A, Sema7A, neuropilin-1 (NP-1), plexin-C1, and β1 integrin in the blood samples of relapsing-remitting multiple sclerosis (RRMS) patients, treated with high-dose interferon-β1a (IFN-β1a), low-dose IFN-β1a, IFN-β1b, and glatiramer acetate (GA) via quantitative real-time polymerase chain reaction (qRT-PCR) assay, and then, compared the results of treatment-naive patients with the healthy controls. The gene expression of Sema3A (P = 0.02), NP-1 (P < 0.001), and plexin-C1 (P < 0.01) significantly decreased in the treatment-naive group, compared to the healthy controls. Sema3A significantly increased in all treated patients, compared to the treatment-naive patients (P < 0.001). However, expression of NP-1 (P < 0.001), plexin-C1 (P < 0.001), and β1 integrin (P < 0.05) only increased in patients receiving high-dose IFN-β1a, IFN-β1b, and GA. Expression of Sema7A increased in only two groups of patients treated with IFN-β1b (P < 0.001) and GA (P = 0.018), without any significant decrease in the treatment-naive group, compared to the healthy controls (P > 0.05). Our findings confirm that the presence of Sema3A, Sema7A, and their receptors can play critical roles in the treatment of MS patients. Therefore, they can be potential target molecules for MS treatment in the future. [ABSTRACT FROM AUTHOR]

• Patients who discontinued treatments after achieving stability appeared to have a more favorable disease course compared to those who ceased treatment for other reasons. • Older age at the time of DMT discontinuation had a favorable impact on relapses, emphasizing the potential importance of considering age-related factors when assessing treatment outcomes in patients with multiple sclerosis and related disorders. • Longer treatment duration might have a potential effect on post-discontinuation outcomes. This retrospective study, conducted between 2005 and 2016, investigated the outcomes of patients with multiple sclerosis (MS) who discontinued injectable first-line disease-modifying therapies (DMTs). The study aimed to identify factors influencing treatment discontinuation and assess the impact of discontinuation on disease progression. Data was collected from 2,270 patients who received injectable DMTs for at least two years and subsequently discontinued treatment due to clinical and MRI remission, side effects, or noncompliance. Patients were categorized into two groups: those stable after discontinuation (SAD) and those with relapse after discontinuation (RAD). Survival analysis and logistic regression were employed to assess factors influencing treatment discontinuation. Of the 60 patients who discontinued DMTs, one-third (n = 20) remained stable, while 40 patients experienced clinical and/or MRI activity during follow-up. The SAD group had a significantly later age at treatment discontinuation compared to RAD patients (35.9 ± 11.1 vs. 30.7 ± 6.1, p = 0.025). Patients below 40 years old had a higher likelihood of experiencing worsening (75 %), while those over 50 years old demonstrated an 80 % stability rate. SAD patients used DMTs for a more extended period than RAD patients (69.1 ± 47.3 vs. 46.6 ± 20.3 months, p = 0.012). A notable proportion (42.9 %) of worsened patients discontinued DMTs without consulting a physician, emphasizing potential challenges in treatment adherence. After treatment discontinuation, RAD patients experienced relapses after a median of 21.0 months. Survival analysis suggested a more favorable disease course for patients who discontinued treatment after achieving a stable period (p = 0.237), with evidence of differentiation between groups after four years. Regression analysis indicated that older age at discontinuation had a favorable impact on relapse probability (HR: 0.904; p = 0.031; 95 % CI: 0.825, 0.991). Reasons for discontinuation unrelated to disease stability showed a positive but imprecise effect on relapse probability. This study provides insights into the outcomes of MS patients discontinuing injectable DMTs, emphasizing the importance of age at discontinuation and reasons for treatment cessation in predicting disease progression. The findings suggest that discontinuation after achieving stability may lead to more favorable outcomes, highlighting the need for personalized treatment decisions in MS management. Further research is warranted to validate these findings and inform clinical practices. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus (MAB) is an emerging, rapidly growing non-tuberculous Mycobacterium causing therapy-resistant pulmonary disease especially in patients with cystic fibrosis (CF). Smooth and rough colony type MAB can be isolated from infected patients whereby rough colony type MAB are more often associated with severe disease. Disease severity is also associated with an alternated type I interferon (IFN-I) response of the MAB-infected patients. However the relevance of this response for the outcome of MAB infection is still unknown. In this study, we analyzed the IFNβ expression of murine macrophages infected with a MAB rough colony strain (MAB-R) isolated from a patient with progressive CF and compared it to macrophages infected with the MAB smooth colony type reference strain (MAB-S). We found that MAB-R infected macrophages expressed significantly more IFNβ mRNA and protein than MAB-S infected macrophages. Higher IFNβ induction by MAB-R was associated with higher TNF expression and intracellular killing while low IFNβ induction was associated with lower TNF expression and persistence of MAB-S. IFNβ induction was independent of the intracellular cGAS-STING recognition pathway. MAB appeared to be recognized extracellularly and induced IFNβ expression via TLR2-TLR4-MyD88-TRIF-IRF3 dependent pathways. By using macrophages lacking the IFN-I receptor we demonstrate that MAB induced IFN-I response essentially contributed to restricting MAB-R and MAB-S infections by activating macrophage Nos2 expression and nitric oxide production. Thus IFN-I seem to influence the intrinsic ability of macrophages to control MAB infections. As MAB persists over long time periods in susceptible patients, our findings suggest that virulence of MAB strains is promoted by an insufficient IFN-I response of the host. [ABSTRACT FROM AUTHOR]

Type I interferon (IFN)-induced genes have the potential for distinguishing active tuberculosis (ATB) from latent TB infection (LTBI) and healthy controls (HC), monitoring treatment, and detection of individuals at risk of progression to active disease. We examined the differential effects of IFN-α, IFN-β and Mycobacterium tuberculosis whole cell lysate (Mtb WCL) stimulation on the expression of selected IFN-stimulated genes in peripheral blood mononuclear cells from individuals with either LTBI, ATB, and healthy controls. Stimulation with IFN-α and IFN-β induced a higher expression of the interrogated genes while Mtb WCL stimulation induced expression similar to that observed at baseline, with the exception of IL-1A and IL-1B genes that were downregulated. The expression of IFN-α-induced FCGR1A gene, IFN-β-induced FCGR1A , FCGR1B , and SOCS3 genes, and Mtb WCL-induced IFI44 , IFI44L , IFIT1 , and IFITM3 genes differed significantly between LTBI and ATB. These findings suggest stimulation-driven gene expression patterns could potentially discriminate LTBI and ATB. Mechanistic studies are necessary to define the processes through which distinct type I IFNs and downstream ISGs determine infection outcomes and identify potential host-directed therapeutic strategies. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-β (IFN-β) production. UreC-mediated activation of the IFN-β pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche. [Display omitted] • Mtb UreC inhibits host DNA repair • UreC interacts with RUVBL2 to impede the DNA repair complex • Mtb UreC-mediated genomic instability induces IFN-β via the cGAS/STING pathway • Heightened IFN-β increases lipid droplet formation, which facilitates Mtb survival Liu et al. show that Mtb UreC interacts with host RUVBL2 to inhibit DNA repair responses, thus triggering genomic instability and micronuclei formation, which activates the cGAS-STING-IRF3 pathway and subsequent IFN-β production. Heightened IFN-β induces the formation of lipid droplets that facilitate the intracellular survival of M. tuberculosis. [ABSTRACT FROM AUTHOR]

Summary Induction of type I interferon (IFN) in response to microbial pathogens depends on a conserved cGAS-STING signaling pathway. The presence of DNA in the cytoplasm activates cGAS, while STING is activated by cyclic dinucleotides (cdNs) produced by cGAS or from bacterial origins. Here, we show that Group B Streptococcus (GBS) induces IFN-β production almost exclusively through cGAS-STING-dependent recognition of bacterial DNA. However, we find that GBS expresses an ectonucleotidase, CdnP, which hydrolyzes extracellular bacterial cyclic-di-AMP. Inactivation of CdnP leads to c-di-AMP accumulation outside the bacteria and increased IFN-β production. Higher IFN-β levels in vivo increase GBS killing by the host. The IFN-β overproduction observed in the absence of CdnP is due to the cumulative effect of DNA sensing by cGAS and STING-dependent sensing of c-di-AMP. These findings describe the importance of a bacterial c-di-AMP ectonucleotidase and suggest a direct bacterial mechanism that dampens activation of the cGAS-STING axis. [ABSTRACT FROM AUTHOR]

Highlights • Interferon-beta is a drug likely to induce Pulmonary Arterial Hypertension. • The earlier Pulmonary Arterial Hypertension diagnosis is confirmed, the better the outcome is. • Neurologists must be suspicious of Pulmonary Arterial Hypertension if dyspnea presents. Abstract 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. [ABSTRACT FROM AUTHOR]

Summary: The chicken and duck are important hosts of Newcastle disease virus (NDV) with distinctive responses to infection. NDV infection in ducks is often subclinical and chronic, while in chickens the infection is clinically apparent and transient. These differences may be due to in part to the host response to NDV infection. This study compares the histopathological changes in the spleen, thymus and bursa of Fabricius following infection with NDV in chickens and ducks. The 9a5b isolate of NDV was inoculated intranasally into specific pathogen-free chickens and Japanese commercial ducks. NDV nucleoprotein (NDV-NP) and interferon (IFN)-β were detected in tissues by immunohistochemistry (IHC), apoptosis was detected by haematoxylin and eosin staining, caspase-3 IHC and the TUNEL assay. Labelling of NDV-NP and lymphoid depletion were most marked in chicken tissues. The pattern of apoptosis in the spleen differed between chickens and ducks. In chickens there were numerous apoptotic cells in the peri-ellipsoidal white pulp and the peri-ellipsoidal, peri-arteriolar and peri-venous lymphoid sheaths, while apoptosis in duck spleens was mainly within the germinal centres. Lymphoid depletion was the main feature in the bursal and thymic tissues of chickens, but apoptosis was marked in these organs in ducks. Expression of IFN-β appeared earlier and was more intense in the tissues from ducks compared with those from chickens. The differences in IFN-β and NDV-NP expression may reflect the relative clinical severity of the infection in the two avian species. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Resistance to angiogenesis inhibition can occur through the upregulation of alternative mediators of neovascularization. We used a combination of angiogenesis inhibitors with different mechanisms of action, interferon-β (IFN-β) and rapamycin, to target multiple angiogenic pathways to treat neuroblastoma xenografts. Methods: Subcutaneous and retroperitoneal neuroblastoma xenografts (NB-1691 and SK-N-AS) were used. Continuous delivery of IFN-β was achieved with adeno-associated virus vector-mediated, liver-targeted gene transfer. Rapamycin was delivered intraperitoneally (5 mg/kg per day). After 2 weeks of treatment, tumor size was measured, and tumor vasculature was evaluated with intravital microscopy and immunohistochemistry. Results: Rapamycin and IFN-β, alone and in combination, had little effect on tumor cell viability in vitro. In vivo, combination therapy led to fewer intratumoral vessels (69% of control), and the remaining vessels had an altered phenotype, being covered with significantly more pericytes (13× control). Final tumor size was significantly less than controls in all tumor models, with combination therapy having a greater antitumor effect than either monotherapy. Conclusion: The combination of IFN-β and rapamycin altered the vasculature of neuroblastoma xenografts and resulted in significant tumor inhibition. The use of combinations of antiangiogenic agents should be further evaluated for the treatment of neuroblastoma and other solid tumors. [Copyright &y& Elsevier]

Abstract: Activation of interferon-β transcription is a highly ordered process beginning with the delivery of NF-κB to the IFN-β enhancer through a process involving stochastic interchromosomal interactions between the IFN-β enhancer and specialized Alu elements. NF-κB delivery is followed by the binding of ATF-2/c-Jun and IRF proteins in a highly cooperative fashion. The assembled “enhanceosome” then recruits PCAF/GCN5 which acetylates the histone tails of the adjacent nucleosomes. The transcriptional coactivator CBP, which binds in a complex with the RNA polymerase II holoenzyme is recruited by the enhanceosome replacing PCAF/GCN5. Next, SWI/SNF, which is part of the holoenzyme complex, induces a conformational change in a nucleosome positioned over the transcriptional start site allowing TFIID to bind, which promotes the sliding of this nucleosome to a new downstream position. At this point the full pre-initiation complex is assembled and transcription commences. This detailed picture of the IFN-β transcription program gathered through years of rigorous studies, now serves as a paradigm for understanding complex transcriptional switches in eukaryotic systems. [Copyright &y& Elsevier]

Background Although old and disordered bones are continuously remodeled with new tissue to maintain their integrity, most bone surfaces are in a non-resorbing state. We hypothesized that osteocytes negatively regulate osteoclast differentiation and function to maintain a non-resorbing state. In the present study, we examined the role of osteocytes in regulating osteoclastogenesis. Highlight When osteoclast precursors were formed from bone marrow cells (BMs) using an macrophage-colony stimulating factor treatment with conditioned medium (CM) from osteocytic MLO-Y4 cells (MLO-Y4-CM), the generated cells exhibited a diminished capacity for osteoclastogenesis. This decreased capability was consistent with increased protein kinase R mRNA expression and decreased c-Fos translation. Furthermore, CM induced phosphorylation of STAT-1 in the osteoclast precursors. To confirm the effect of the MLO-Y4-CM, we prepared non-osteocytic cell-free osteocyte-enriched bone fragments (OEBFs). OEBFs, as well as MLO-Y4-CM, reduced the commitment of BMs into osteoclast precursors. These effects were partially abrogated by an anti-interferon (IFN)-β neutralizing antibody. Indeed, the MLO-Y4 cells and primary osteocytes embedded in the OEBFs expressed more IFN-β than osteoclast lineage cells. Conclusion We found that osteocytes secrete IFN-β as an inhibitory factor of osteoclastogenesis. Our findings provide a new insight into the mechanisms underlying the osteocytic regulation of bone remodeling. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To provide a detailed profile of the peripheral IGF system in the neurological conditions; amyotrophic lateral sclerosis (ALS), post polio syndrome (PPS) and multiple sclerosis (MS). To determine whether subsets of patients within the disease groups could be identified in whom one or more components of the IGF regulatory system are altered compared to healthy control subjects matched for age, sex and BMI. Design: Three cohorts of patients were recruited, 28 with ALS, 18 with PPS and 23 with MS. Patients were individually matched to a healthy control based on sex, age (±3yr), and BMI (±2.5kg·m−2). The concentration (ng/ml) of serum IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and acid-labile subunit (μg/ml) was determined by IRMA. Results: In ALS patients, there was an increase of 11% in [IGFTOTAL] (p =0.042) ([IGFTOTAL]=[IGF-I]+[IGF-II]) and [IGFBP-1] was decreased by 34% (p =0.050) compared to matched controls. In “surviving” ALS patients, defined as those ALS patients with long disease duration (+2 SD from the mean survival time for Irish patients post diagnosis), there was an increase in [IGF-I] 36% (p =0.032) and a large decrease in [IGFBP-1] –58% (p =0.020) compared to controls. These differences were not evident in pre-agonal ALS patients. The concentration of serum IGF-I was 38% (p =0.018), acid-labile subunit 17% (p =0.044) and IGFBP-2 43% (p =0.035) higher in MS patients compared to controls. When stratified for interferon-beta (IFN-β) use, we observed an increase in serum [IGF-I] 52% (p =0.013) and [IGFTOTAL] 19% (p =0.043) in MS patients undergoing IFN-β treatment, but MS patients not undergoing IFN-β treatment had similar IGF and IGFBP concentration to controls. Serum [IGFBP-3] 18% (p =0.033), [IGFBP-2] 86% (p =0.015) and (acid-labile subunit) 33% (p =0.012) was also higher in IFN-β patients compared to controls. Stratified by stage of disease the most significant increase in components of the peripheral IGF system was attributed to relapsing-remitting MS patients treated with IFN-β. All components of the peripheral IGF system in PPS patients were similar to controls. Conclusions: The increase in circulating IGF-I and a reduction in regulatory binding protein IGFBP-1 in ALS patients with a “stable” disease profile suggest a potential change in peripheral IGF bioavailability in these subjects. In MS, we report a change in a number of components of the peripheral IGF system, the observed increase in IGF-I in patients treated with IFN-β being of most significance as a potential therapeutic biomarker. [Copyright &y& Elsevier]

Abstract: We report a patient with multiple sclerosis (MS) who developed subcutaneous nodules on the face, shoulders and extremities while being treated with interferon (IFN)-β-1b. These nodules fluctuated in parallel with myelopathy, and were diagnosed as lupus erythematosus profundus (LEP) based on histopathological findings. The patient showed no relapse of either neurological symptoms or subcutaneous nodules after cessation of IFN-β-1b. This agent can cause induration and necrosis in the sites of injection but also systemic skin lesions such as LEP ascribable to its immunomodulatory effects. [Copyright &y& Elsevier]

The article discusses the significance of recognizing individual differences in arteriogenesis. It argues that in emerging cardiovascular therapeutic approaches, there is a lack of standard patient profiling and individualizing therapies. It highlights on the study of patients with collateral growth response to coronary disease, using microarray analysis. Moreover, challenges for individualized therapies in arteriogenesis and angiogenesis are also discussed.