Interferon Β1 Research Articles

Heart-specific NFAT5 knockout suppresses type I interferon signaling and aggravates coxsackievirus-induced myocarditis.

Nuclear factor of activated T cells 5 (NFAT5) is an osmosensitive transcription factor that is well-studied in renal but rarely explored in cardiac diseases. Although the association of Coxsackievirus B3 (CVB3) with viral myocarditis is well-established, the role of NFAT5 in this disease remains largely unexplored. Previous research has demonstrated that NFAT5 restricts CVB3 replication yet is susceptible to cleavage by CVB3 proteases. Using an inducible cardiac-specific Nfat5-knockout mouse model, we uncovered that NFAT5-deficiency exacerbates cardiac pathology, worsens cardiac function, elevates viral load, and reduces survival rates. RNA-seq analysis of CVB3-infected mouse hearts revealed the significant impact of NFAT5-deficiency on gene pathways associated with cytokine signaling and inflammation. Subsequent in vitro and in vivo investigation validated the disruption of the cytokine signaling pathway in response to CVB3 infection, evidenced by reduced expression of key cytokines such as interferon β1 (IFNβ1), C-X-C motif chemokine ligand 10 (CXCL10), interleukin 6 (IL6), among others. Furthermore, NFAT5-deficiency hindered the formation of stress granules, leading to a reduction of important stress granule components, including plakophilin-2, a pivotal protein within the intercalated disc, thereby impacting cardiomyocyte structure and function. These findings unveil a novel mechanism by which NFAT5 inhibits CVB3 replication and pathogenesis through the promotion of antiviral type I interferon signaling and the formation of cytoplasmic stress granules, collectively identifying NFAT5 as a new cardio protective protein.

Effect of Haoqin Qingdan Tang on influenza A virus through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway

ObjectiveInfluenza, a viral respiratory illness, leads to seasonal epidemics and occasional pandemics. Given the rising resistance and adverse reactions associated with anti-influenza drugs, Traditional Chinese Medicine (TCM) emerges as a promising approach to counteract the influenza virus. Specifically, Haoqin Qingdan Tang (HQQDT), a TCM formula, has been employed as an adjuvant treatment for influenza in China. However, the active compounds and underlying mechanisms of HQQDT remain unknown. AimThe aim of this study was to investigate HQQDT's antiviral and anti-inflammatory activities in both in vivo and in vitro, and further reveal its active ingredients and mechanism. MethodsIn vivo and in vitro experiments were conducted to verify the antiviral and anti-inflammatory activities of HQQDT. Subsequently, the active ingredients and mechanism of HQQDT were explored through combining high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS) analysis and network pharmacology. Finally, the examinations of cell cytokines and signaling pathways aimed to elucidate the predicted mechanisms. ResultsThe results indicated that HQQDT exhibited inhibitory effects on influenza viruses A/PR/8/34 (H1N1), A/HK/1/68 (H3N2), and A/California/4/2009 (H1N1) in vitro. Furthermore, HQQDT enhanced the survival rate of influenza-infected mice, reduced the lung index and lung virus titer, and mitigated lung tissue damage in vivo. The proinflammatory cytokine expression levels upon influenza virus infection in PR8-induced A549 cells or mice were suppressed by HQQDT, including IL-6, IL-1β, CCL2, CCL4, IP-10, interferon β1 (IFN-β1), the interferon regulatory factor 3 (IRF3), and hemagglutinin (HA). Twenty-two active components of HQQDT against influenza were identified using HPLC-Q-TOF-MS analysis. Based on network pharmacological predictions, the JAK/STAT signaling pathway is considered the most relevant for HQQDT's action against influenza. Finally, western blot assays revealed that HQQDT regulated the protein level of the JAK/STAT signaling pathway in PR8-infected A549 cells and lung tissue. ConclusionThese findings verified the antiviral and anti-inflammatory effects of HQQDT through JAK-STAT signaling pathway in influenza infections, laying the foundation for its further development.

Rose Bengal Photodynamic Therapy (RB-PDT) Modulates the Inflammatory Response in LPS-Stimulated Human Corneal Fibroblasts By Influencing NF-κB and p38 MAPK Signaling Pathways

Purpose To investigate the effect of rose bengal photodynamic therapy on lipopolysaccharide-induced inflammation in human corneal fibroblasts. Furthermore, to analyze potential involvement of the mitogen-activated protein kinase and nuclear factor kappa B signaling pathways in this process. Methods Human corneal fibroblast cultures underwent 0–2.0 µg/mL lipopolysaccharide treatment, and 24 h later rose bengal photodynamic therapy (0.001% RB, 565 nm wavelength illumination, 0.17 J/cm2 fluence). Interleukin-6, interleukin-8, intercellular adhesion molecule-1, interferon regulatory factor-3, interferon α2, and interferon β1 gene expressions were determined by quantitative PCR. Interleukin-6, interleukin-8, and C-C motif chemokine ligand-4 concentrations in the cell culture supernatant were measured by enzyme-linked immunosorbent assays and intercellular adhesion molecule-1 protein level in human corneal fibroblasts by western blot. In addition, the nuclear factor kappa B and mitogen-activated protein kinase signaling pathways were investigated by quantitative PCR and phosphorylation of nuclear factor kappa B p65 and p38 mitogen-activated protein kinase by western blot. Results Rose bengal photodynamic therapy in 2.0 µg/mL lipopolysaccharide-stimulated human corneal fibroblasts triggered interleukin-6 and interleukin-8 mRNA (p < .0001) and interleukin-6 protein increase (p < .0001), and downregulated intercellular adhesion molecule-1 expression (p < .001). C-C motif chemokine ligand-4, interferon regulatory factor-3, interferon α2, and interferon β1 expressions remained unchanged (p ≥ .2). Rose bengal photodynamic therapy increased IκB kinase subunit beta, nuclear factor kappa B p65, extracellular signal-regulated kinases-2, c-Jun amino terminal kinase, and p38 transcription (p ≤ .01), and triggered nuclear factor kappa B p65 and p38 mitogen-activated protein kinase phosphorylation (p ≤ .04) in lipopolysaccharide treated human corneal fibroblasts. Conclusion Rose bengal photodynamic therapy of lipopolysaccharide-stimulated human corneal fibroblasts can modify the inflammatory response by inducing interleukin-6 and interleukin-8 expression, and decreasing intercellular adhesion molecule-1 production. C-C motif chemokine ligand-4, interferon regulatory factor-3, and interferon α and β expressions are not affected by rose bengal photodynamic therapy in these cells. The underlying mechanisms may be associated with nuclear factor kappa B and p38 mitogen-activated protein kinase pathway activation.

Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cells

Mitochondrial dysfunction is important in various chronic degenerative disorders, and aberrant immune responses elicited by cytoplasmic mitochondrial DNA (mtDNA) may be related. Here, we developed mtDNA-targeted MTERF1-FokI and TFAM-FokI endonuclease systems to induce mitochondrial DNA double-strand breaks (mtDSBs). In these cells, the mtDNA copy number was significantly reduced upon mtDSB induction. Interestingly, in cGAS knockout cells, synthesis of interferon β1 and interferon-stimulated gene was increased upon mtDSB induction. We found that mtDSBs activated DNA-PKcs and HSPA8 in a VDAC1-dependent manner. Importantly, the mitochondrial E3 ligase MARCH5 bound active DNA-PKcs in cells with mtDSBs and reduced the type І interferon response through the degradation of DNA-PKcs. Likewise, mitochondrial damage caused by LPS treatment in RAW264.7 macrophage cells increased phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA in a DNA-PKcs-dependent manner. Accordingly, in March5 knockout macrophages, phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA were prolonged after LPS stimulation. Together, cytoplasmic mtDNA elicits a cellular immune response through DNA-PKcs, and mitochondrial MARCH5 may be a safeguard to prevent persistent inflammatory reactions.

IFNβ1 secreted by breast cancer cells undergoing chemotherapy reprograms stromal fibroblasts to support tumour growth after treatment.

Chemotherapy (CTX) remains the standard of care for most aggressive tumours, including breast cancer (BC). In BC chemotherapeutic regimens, the maximum tolerated dose of cytotoxic drugs is administered at regular intervals, and cancer cells can re‐grow or adapt during the resting periods between cycles. The impact of the tumour microenvironment on the fate of cancer cells after CTX remains poorly understood. Here, we show that paracrine signalling from CTX‐treated cancer cells to stromal fibroblasts can drive cancer cell recovery after cytotoxic drug withdrawal. Interferon β1 (IFNβ1) secreted by cancer cells following treatment with high doses of CTX instigates the acquisition of an anti‐viral state in stromal fibroblasts. This state is associated with an expression pattern here referred to as interferon signature (IFNS), which encompasses several interferon‐stimulated genes (ISGs), including numerous pro‐inflammatory cytokine genes. This crosstalk is an important driver of the expansion of BC cells after CTX, and IFNβ1 blockade in tumour cells abrogated their fibroblast‐dependent recovery potential. Analysis of human breast carcinomas supported a link between CTX‐induced IFNS in tumour stroma and poor response to CTX treatment. First, IFNβ1 expression in human breast carcinomas was found to inversely correlate with recurrence free survival (RFS). Second, using laser capture microdissection data sets, we show a higher expression of IFNS in the stromal tumour compartment compared to the epithelial one and this signature was found to be more prominent in more aggressive subtypes of BC (basal‐like), pointing to a pro‐tumorigenic role of this signature. Moreover, IFNS was associated with higher recurrence rates and a worse outcome in BC patients. Our study unravels a novel form of paracrine communication between cancer cells and fibroblasts that ultimately results in CTX resistance. Targeting this axis has the potential to improve CTX outcomes in patients with BC.

A Long Non-coding RNA IVRPIE Promotes Host Antiviral Immune Responses Through Regulating Interferon β1 and ISG Expression.

Accumulating studies have shown that long non-coding RNAs (lncRNAs) modulate multiple biological processes, including immune response. However, the underlying mechanisms of lncRNAs regulating host antiviral immune response are not well elucidated. In this study, we report that analysis of the existing dataset transcriptome of blood immune cells of patients with influenza A virus (IAV) infection and after recovery (GSE108807) identified a novel lncRNA, termed as IVRPIE (Inhibiting IAV Replication by Promoting IFN and ISGs Expression), was involved in antiviral innate immunity. In vitro studies showed that IVRPIE was significantly upregulated in A549 cells after IAV infection. Gain-and-loss of function experiments displayed that enforced IVRPIE expression significantly inhibited IAV replication in A549 cells. Conversely, silencing IVRPIE promoted IAV replication. Furthermore, IVRPIE positively regulates the transcription of interferon β1 and several critical interferon-stimulated genes (ISGs), including IRF1, IFIT1, IFIT3, Mx1, ISG15, and IFI44L, by affecting histone modification of these genes. In addition, hnRNP U was identified as an interaction partner for IVRPIE. Taken together, our findings suggested that a novel lncRNA IVRPIE is a critical regulator of host antiviral response.

Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes.

PurposeThe purpose of this study was to assess characteristics of SJ-815, a novel oncolytic vaccinia virus lacking a functional thymidine kinase-encoding TK gene, and instead, having two human transgenes: the IFNB1 that encodes interferon β1, and the CES2 that encodes carboxylesterase 2, which metabolizes the prodrug, irinotecan, into cytotoxic SN-38.Materials and MethodsViral replication and dissemination of SJ-815 were measured by plaque assay and comet assay, respectively, and compared to the backbone of SJ-815, a modified Western Reserve virus named WI. Tumor cytotoxicity of SJ-815 (or mSJ-815, which has the murine IFNB1 transgene for mouse cancers) was evaluated using human and mouse cancer cells. Antitumor effects of SJ-815, with/without irinotecan, were evaluated using a human pancreatic cancer-bearing mouse model and a syngeneic melanoma-bearing mouse model. The SN-38/irinotecan ratios in mouse melanoma tissue 4 days post irinotecan treatment were compared between groups with and without SJ-815 intravenous injection.ResultsSJ-815 demonstrated significantly lower viral replication and dissemination, but considerably stronger in vitro tumor cytotoxicity than WI. The combination use of SJ-815 plus irinotecan generated substantial tumor regression in the human pancreatic cancer model, and significantly prolonged survival in the melanoma model (hazard ratio, 0.11; 95% confidence interval, 0.02 to 0.50; p=0.013). The tumor SN-38/irinotecan ratios were over 3-fold higher in the group with SJ-815 than those without (p < 0.001).ConclusionSJ-815 demonstrates distinct characteristics gained from the inserted IFNB1 and CES2 transgenes. The potent antitumor effects of SJ-815, particularly when combined with irinotecan, against multiple solid tumors make SJ-815 an attractive candidate for further preclinical and clinical studies.

Long non-coding RNA PSMB8-AS1 regulates influenza virus replication

ABSTRACTLong non-coding RNAs (lncRNAs) are a new arm of gene regulatory mechanism as discovered by sequencing techniques and follow-up functional studies. There are only few studies on lncRNAs as related to gene expression regulation and anti-viral activity during influenza virus infection. We sought to identify and characterize lncRNAs involved in influenza virus replication. Using RNA sequencing analysis, we found that 1,912 lncRNAs were significantly changed in human lung epithelial A549 cells infected with influenza A/Puerto Rico/8/34. Gene ontology analysis on neighboring genes of these lncRNAs revealed that the genes involved in type I interferon signaling and cellular response were highly enriched. Seven selected up-regulated lncRNAs (AC015849.2, RP-1-7H24.1, PSMB8-AS1, CTD-2639E6.9, PSOR1C3, AC007283.5 and RP11-670E13.5) were verified by real-time PCR. These lncRNAs were also induced by other two influenza H1N1 virus strains (A/WSN/1933 and A/Oklahoma/3052/09) and interferon β1. Repression of PSMB8 antisense RNA 1 (PSMB8-AS1) using CRISPR interference reduced viral mRNA and protein levels as well as the release of progeny influenza virus particles. Our study suggests that lncRNA PSMB8-AS1 could be a new host factor target for developing antiviral therapy against influenza virus infection.

Krüppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling.

Expression of the transcription factor Krüppel-like factor 9 (KLF9) is frequently reduced in colorectal cancers, although a tumor suppressive role has not been established. To determine if KLF9 suppresses intestinal adenoma formation, we generated mice of distinct Klf9 genotypes in the background of the Apc (Min/+) mouse and compared their adenoma burdens at 16 weeks of age. While small intestine adenoma burden remained unchanged among Klf9 genotypes, male and female Apc(Min/+)/Klf9(-/-) and Apc(Min/+)/Klf9(+/-) mice exhibited significantly more colon adenomas than their Apc(Min/+)/Klf9(+/+) counterparts. Microarray analysis showed significant increases in the expression of interferon-induced genes in the colon mucosa of female Apc (Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-) compared to Apc(Min/+)/Klf9(+/+) mice, prior to overt adenoma occurrence. Gene upregulation was confirmed by qPCR of colon mucosa and by siRNA knockdown of KLF9 in human HT29 colorectal cancer cells. Increases in expression of these genes were further augmented by supplementation with Interferon β1. Circulating levels of the cytokine, interferon-stimulated gene 15 (ISG15) were increased in Apc(Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-) mice relative to Apc(Min/+)/Klf9(+/+). Additionally, colon mucosal levels of ISG15 were increased in Apc(Min/+)/Klf9(+/-) mice. Chromatin immunoprecipitation demonstrated KLF9 recruitment to the ISG15 promoter. Lastly, treatment with ISG15 suppressed apoptosis in HT29 cells, in the presence and absence of 5-fluorouracil (5FU). Results show KLF9 to be a haploinsufficient suppressor of colon tumorigenesis in Apc(Min/+) mice in part, by repression of ISG15 and the latter's antiapoptotic function. Krüppel-like factor 9 (KLF9) is a haploinsufficient tumor suppressor in the ApcMin/+ mouse colon by suppressing expression of ISG15, an apoptosis-inhibiting cytokine.

Abstract 4091: Interfering with interferon: An axis of ATF2-mediated chemoresistance

Abstract Malignant melanoma is currently the most lethal skin cancer and comprises approximately 8% of total U.S. cancers cases. Despite the advent of even the most effective targeted monotherapies to date (e.g., mutant B-RAF inhibitors), clinical responses have largely been transient, as melanomas rapidly develop therapeutic resistance, highlighting the need to target other critical signaling pathways. In melanoma, Activating Transcription Factor 2 (ATF2) elicits an oncogenic function when nuclear but a tumor suppressor function when it is cytosolic/mitochondrial. In progressively malignant melanoma, increased PKCϵ-mediated phosphorylation of ATF2 on threonine 52 (T52) promotes its nuclear localization and transcriptional activity, and renders the cells more resistant to genotoxic stress. To determine how PKCϵ-phosphorylated ATF2 contributes to melanoma biology, we performed gene expression profiling of melanoma cells that were reconstituted with wild-type, T52 phosphomutant or phosphomimic ATF2, in the presence or absence of genotoxic stress (which attenuates the T52 phosphorylation of ATF2). We report that in melanoma cells, genotoxic stress induces the expression of a cluster of Interferon β1 (IFNβ1) and related genes, which is suppressed by the expression of ATF2T52E. ATF2 binds to the 5′-promoter region of IFNβ1, and we identified the ATF2/AP-1 binding site required for transcriptional repression. The stress-induced expression of IFNβ1 mediates S-phase accumulation during genotoxic stress with a concomitant induction of a senescence-like phenotype. In contrast, blockade of type-1 interferon signaling by shRNA-mediated depletion of the IFNAR receptor abrogates the S-phase accumulation, blocking cells in G1 phase and reducing the extent of stress-induced cell death. The expression of or treatment with exogenous IFNβ1 blunts the proliferation of melanoma cells in both 2- and 3-dimensional spheroid cultures. Notably, the treatment of melanoma cells with mutant BRAF inhibitor (Vemurafenib/PLX4720) also induces the expression of IFNβ1 and senescence markers, and the co-treatment of melanoma cells with IFNβ1 and etoposide or PLX4720 significantly enhances the cell death induced by either etoposide or PLX4720 alone. Lastly, we found that the stress-induced IFNβ1 expression by melanoma cells elicits paracrine effects, enhancing the melanoma cell clearance by lymphocytes in an in vitro co-culture system. Our data demonstrate a novel transcriptional regulatory role exhibited by ATF2 on IFNβ1, which influences cell cycle dynamics and stress/treatment resistance of melanoma cells. The therapeutic and prognostic implications of these findings will be discussed. Citation Format: Eric Lau, Giuseppina Claps, David S. Hoon, Ze'ev A. Ronai. Interfering with interferon: An axis of ATF2-mediated chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4091. doi:10.1158/1538-7445.AM2014-4091

The Editor takes a closer look at some of this month's articles

Clinical & Experimental AllergyVolume 43, Issue 10 p. 1091-1091 Editor's ChoiceFree Access The Editor takes a closer look at some of this month's articles First published: 16 September 2013 https://doi.org/10.1111/cea.12190AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Maternal Vitamin D: no association with allergic outcomes in offspring The debate about the role of vitamin D and allergic disease continues to attract a lot of attention 1. Wills and colleagues (pp. 1180–1188) contribute to the discussion with a large epidemiological study of white caucasians relating maternal vitamin D levels to a range of allergic outcomes in their offspring up to 9 years of age. No relationship was found with any allergy related outcome. Only 5% of mothers were deficient in vitamin D with ~30% having insufficient levels of the vitamin. While this study doesn't therefore exclude the possibility that severe vitamin D deficiency can lead to an increased risk of allergic disease, it would seem unlikely that there is a strong link between maternal vitamin D and the risk of childhood allergy. Dr. Andrew Wills Vitamin D Structure (Photo credit: Nwanneka123/Wikimedia Commons). Interferon regulatory factor 1: a role in bronchitis but not asthma? Interferon regulatory factor 1 (IRF-1) is a member of a family of transcription factors that regulate interferon β1 and interferon γ expression as well a differentiation of T cells. Pinto et al. (pp. 1152–1159), demonstrate in this issue a link between polymorphisms in the IRF-1 gene and the risk of developing bronchitis in two cohorts of children. Associations with asthma and airway hyperresponsiveness (AHR) were found in one cohort but not the replication cohort (AHR was not measured). The odds ratios were modest, but it is interesting that the authors were able to genetically dissociate asthma from recurrent bronchitis. This emphasizes that the factors that control airway responses to viruses in childhood are distinct from those associated with asthma. It would be interesting to link the IRF-1 genotype with the endotypes of childhood asthma which are being revealed by epidemiological studies of childhood wheeze 2, 3. Professor Leonardo A. Pinto IRF4 gene map (yellow) with 9 exons (rectangles) and the 3UTR (grey). [See figure 1 in L. A. Pinto et al. (pp. 1152–1159)]. Egg allergy: to challenge or not to challenge Egg allergy is common in early childhood with large effects on dietary restriction. Many children who react to lightly cooked egg can tolerate egg contained in baked products. At the moment only a challenge test can reliably distinguish between the two types of reaction which is burdensome both for the doctor and parent-child. Tan et al. (pp. 1189–1195) have asked whether skin prick tests using either baked muffin or ovomucoid are sufficiently predictive to avoid the need for challenge with a baked egg product. They show that a < 2 mm reaction to the muffin meant that there was an 88% chance of a negative challenge and perhaps even more usefully if there was a > 11 mm wheal to ovomucoid there was a 100% chance of a positive challenge. The practical implications of this for allergist and parent are discussed in an excellent editorial by Wanda Phipatanakul (pp. 1095–1096). Dr. John W Tan Professor Wanda Phipatanakul Blueberry muffin (Photo credit: NCI, Renee Cornet/Wikimedia Commons). References 1Reinholz M, Ruzicka T, Schauber J. Vitamin D and its role in allergic disease. Clin Exp Allergy 2012; 42: 817– 26. 2Spycher BD, Silverman M, Kuehni CE. Phenotypes of childhood asthma: are they real? Clin Exp Allergy 2010; 40: 1130– 41. 3Caliskan M, Bochkov YA, Kreiner-Moller E et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med 2013; 368: 1398– 407. Caption to cover illustration: House dust mites (Dermatophagoides pteronyssinus), by photographer Gilles San Martin/Wikimedia Commons. This logo highlights the Editor's Choice articles on the cover and the first page of each of the articles. Volume43, Issue10October 2013Pages 1091-1091 ReferencesRelatedInformation

Genetics of Asthma Exacerbations: A Candidate Gene and Genome-Wide Association Study

RationaleExacerbations are a major cause of asthma morbidity and account for a large proportion of asthma healthcare costs. Discovering genetic markers of susceptibility to exacerbations could result in more targeted interventions.MethodsUsing data from four clinical trials (ADA109055/ADA109057/ SFA103153/I13106870) 701 samples were analyzed to conduct a genome-wide association study (GWAS) and an analysis of 50 markers from 18 candidate genes. Exacerbation cases were defined as subjects requiring treatment with systemic corticosteroids, an emergency room visit, or hospitalization for acute asthma symptoms. Controls were subjects without exacerbations. Meta-analysis was used to combine logistic regression results across studies. Principal components derived from genome-wide genetic markers accounted for ancestral diversity.ResultsNo genetic markers from candidate gene or GWAS analyses met pre-specified significance criteria (2.0x10−4 and 4.1x10−8, respectively) for association with asthma exacerbations. However, results from two candidate genes merited additional consideration. Although the direction of effect differed among studies, correlated coding variants in the IL-4 receptor gene (IL4R), a gene previously associated with asthma exacerbations, had the lowest meta-p-values across three studies (p <0.005). A single genetic effect was detected for interferon β1 (IFNB1) with exacerbations in the study that recruited only African-Americans (p<0.002).ConclusionsWhile no genetic markers met the pre-specified statistical criteria, two genes of interest were identified. The IL4R results may support previous findings of association with the IL-4/IL-13 pathway. Similarly, IFNB1 findings in African-Americans are consistent with innate immunity pathways contributing to asthma exacerbation susceptibility. Further studies are required to understand exacerbation associations. RationaleExacerbations are a major cause of asthma morbidity and account for a large proportion of asthma healthcare costs. Discovering genetic markers of susceptibility to exacerbations could result in more targeted interventions. Exacerbations are a major cause of asthma morbidity and account for a large proportion of asthma healthcare costs. Discovering genetic markers of susceptibility to exacerbations could result in more targeted interventions. MethodsUsing data from four clinical trials (ADA109055/ADA109057/ SFA103153/I13106870) 701 samples were analyzed to conduct a genome-wide association study (GWAS) and an analysis of 50 markers from 18 candidate genes. Exacerbation cases were defined as subjects requiring treatment with systemic corticosteroids, an emergency room visit, or hospitalization for acute asthma symptoms. Controls were subjects without exacerbations. Meta-analysis was used to combine logistic regression results across studies. Principal components derived from genome-wide genetic markers accounted for ancestral diversity. Using data from four clinical trials (ADA109055/ADA109057/ SFA103153/I13106870) 701 samples were analyzed to conduct a genome-wide association study (GWAS) and an analysis of 50 markers from 18 candidate genes. Exacerbation cases were defined as subjects requiring treatment with systemic corticosteroids, an emergency room visit, or hospitalization for acute asthma symptoms. Controls were subjects without exacerbations. Meta-analysis was used to combine logistic regression results across studies. Principal components derived from genome-wide genetic markers accounted for ancestral diversity. ResultsNo genetic markers from candidate gene or GWAS analyses met pre-specified significance criteria (2.0x10−4 and 4.1x10−8, respectively) for association with asthma exacerbations. However, results from two candidate genes merited additional consideration. Although the direction of effect differed among studies, correlated coding variants in the IL-4 receptor gene (IL4R), a gene previously associated with asthma exacerbations, had the lowest meta-p-values across three studies (p <0.005). A single genetic effect was detected for interferon β1 (IFNB1) with exacerbations in the study that recruited only African-Americans (p<0.002). No genetic markers from candidate gene or GWAS analyses met pre-specified significance criteria (2.0x10−4 and 4.1x10−8, respectively) for association with asthma exacerbations. However, results from two candidate genes merited additional consideration. Although the direction of effect differed among studies, correlated coding variants in the IL-4 receptor gene (IL4R), a gene previously associated with asthma exacerbations, had the lowest meta-p-values across three studies (p <0.005). A single genetic effect was detected for interferon β1 (IFNB1) with exacerbations in the study that recruited only African-Americans (p<0.002). ConclusionsWhile no genetic markers met the pre-specified statistical criteria, two genes of interest were identified. The IL4R results may support previous findings of association with the IL-4/IL-13 pathway. Similarly, IFNB1 findings in African-Americans are consistent with innate immunity pathways contributing to asthma exacerbation susceptibility. Further studies are required to understand exacerbation associations. While no genetic markers met the pre-specified statistical criteria, two genes of interest were identified. The IL4R results may support previous findings of association with the IL-4/IL-13 pathway. Similarly, IFNB1 findings in African-Americans are consistent with innate immunity pathways contributing to asthma exacerbation susceptibility. Further studies are required to understand exacerbation associations.

Systemic lupus erythematosus induced by interferon β1 therapy in a patient with multiple sclerosis

Drug-induced lupus erythematosus is defined as a lupus-like syndrome temporally related to a drug exposure. We report a 34-year-old woman with multiple sclerosis who developed, while being treated with interferon β-1a, myalgia and associated with wrist synovitis. Clinical and immunologic investigations were in favor of systemic lupus erythematosus. Interferon therapy was maintained. Under corticosteroids and antipaludeen treatment, the patient did not develop any other lupic manifestations.

Role of TLR4 in ethanol effects on innate and adaptive immune responses in peritoneal macrophages

Toll-like receptors (TLRs) play an important role in the innate immune response and these receptors link innate and adaptive responses. We have reported that ethanol modulates TLR4 receptors by activating or inhibiting its response. However, the role of TLRs in the effects of ethanol on the innate and adaptive responses during acute or chronic treatment is presently unknown. Peritoneal macrophages of wild-type and TLR4-deficient mice treated with acute ethanol (4 g kg(-1), intraperitoneally) or chronic ethanol consumption (5 months) were used. Here we report how acute ethanol dose induces inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, macrophage inflammatory protein 1α (MIP-1α), interferon β1 and IL-12β) and chemokines (monocyte chemoattractant protein -1α and MIP-1α), and upregulates major histocompatibility complexes class I and II (MHC-I and -II), but inhibits the activation of the costimulatory molecules (CD86 and CD40), leading to the suppression of the CD4(+) T-cell proliferation in the macrophages of wild-type mice. Chronic ethanol consumption downregulates the number of F4/80(+) cells expressing MHC-I and -II and decreases CD4(+) T-cell activation in wild-type mice. Interestingly, elimination of TLR4 abolishes the effects of ethanol on the innate and the adaptive inflammatory response induced by both ethanol treatments in macrophages. Taken together, our findings support the role of TLR4 in the effects of ethanol on the immune system, and suggest that alterations in the function of this receptor might modulate the immune response induced by alcohol abuse.

Bronchiolitis obliterans with organising pneumonia during interferon β-1a treatment

A 49-year-old man with an 8-year history of multiple sclerosis was prescribed treatment with interferon β1 a (IFNβ1a) (Avonex, Biogen), 30 mg per week. 3 months later he presented with a progressive, unproductive cough and right hemithoracic pain without fever. Full blood count showed slight leucocytosis (13 × 109 cells/L) with 75% neutrophils. The erythrocyte sedimentation rate was raised (50 mm/h). Chest radiography revealed an alveolar opacity in the right inferior lobe, which expanded progressively over 10 days.

Involvement of interferon β1 and 2′5′ oligoadenylate synthetase in the process of interleukin 6- and leukemia inhibitory factor-induced differentiation of murine myeloid leukemia cells

Involvement of interferon β1 and 2′5′ oligoadenylate synthetase in the process of interleukin 6- and leukemia inhibitory factor-induced differentiation of murine myeloid leukemia cells