Interferon Regulatory Factor Research Articles

Immature functional development of lumbar locomotor networks in adult Irf8-/- mice.

To date, research on the role of the brainstem and spinal cord in motor behavior has relied on in vitro preparations of the neonatal rodent spinal cord, with or without the brainstem; their spatial and temporal scope are subject to technical limitations imposed by low oxygen tension in deep tissues. Therefore, we created an arterially perfused in situ preparation that allowed us to investigate functional interactions in the CNS from the neonatal to adult period. Decerebrated rodents were kept alive via total artificial cardiopulmonary bypass for extracorporeal circulation; the plasma oxygen and ion components needed for survival were supplied through the blood vessels. Interferon regulatory factor 8 (IRF8) is a transcription factor that promotes myeloid cell development and stimulates innate immune responses. In the brain, IRF8 is expressed only in microglia and directs the expression of many genes that serve microglial functions. Recent evidence indicates that IRF8 affects behavior and modulates Alzheimer's disease progression in a mouse model. However, whether this immune deficiency arising from the absence of IRF8 influences the development of the neuronal network in the spinal cord is unknown. We applied the above methodology to mice of all ages and electrophysiologically explored whether the absence of IRF8 influences the development of lumbar central pattern generator (CPG) networks. In mice of all ages, bilateral neuronal discharges by the normal CPG networks activated by the modulated sympathetic tone via descending pathways at high flow rates became organized into discharge episodes punctuated by periods of quiescence. Similar discharge episodes were generated by the adult CPG networks (≥P14 days) activated by drug application. However, discharge episodes elicited by activating the neonatal-juvenile CPG networks (<P14 days) occurred alternately on the left and right sides. Interestingly, discharge episodes elicited by the CPG networks in adult IRF8 knockout mice (P11-12 weeks) consisted of those elicited by the CPG networks of both periods. Thus, it was suggested that growing up with immunodeficiency due to loss of IRF8 might interfere with the normal development of functions exerted by the lumbar CPG network because IRF8 plays a role in the normal development of the lumbar CPG network.

IRF5 governs macrophage adventitial infiltration to fuel abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by the expansion of the aortic wall. One of the most significant features is the infiltration of macrophages in the adventitia, which drives vasculature remodeling. The role of macrophage-derived interferon regulatory factor 5 (IRF5) in macrophage infiltration and AAA formation remains unknown. RNA sequencing of AAA adventitia identified Irf5 as the top significantly increased transcription factor that is predominantly expressed in macrophages. Global and myeloid cell-specific deficiency of Irf5 reduced AAA progression, with a marked reduction in macrophage infiltration. Further cellular investigations indicated that IRF5 promotes macrophage migration by direct regulation of downstream phosphoinositide 3-kinase γ (PI3Kγ, Pik3cg). Pik3cg ablation hindered AAA progression, and myeloid cell-specific salvage of Pik3cg restored AAA progression and macrophage infiltration derived from Irf5 deficiency. Finally, we found that IRF5 and PI3Kγ expression in the adventitia is significantly increased in patients with AAA. These findings reveal that the IRF5-dependent regulation of PI3Kγ is essential for AAA formation.

Interferon-Gamma-Inducible Protein 16 Inhibits Hepatocellular Carcinoma via Interferon Regulatory Factor 3 on Chemosensitivity.

Previous reports have suggested IFI16 as a tumor suppressor in hepatocellular carcinoma (HC). Nonetheless, the biological significance of IFI16 and its mechanism concerning resistance to cisplatin (DDP) in HC requires further exploration. Samples of tumor and corresponding para-carcinoma tissues were acquired from patients with HC. Furthermore, DDP-resistant cell lines of HC, specifically HCC, Huh7 and Hepatoblastoma, HepG3, were generated by gradually increasing the concentration of DDP. Cell apoptosis and DNA damage were evaluated by utilizing flow cytometry assay and TUNEL staining. The interaction between IFI16 and interferon regulatory factor 3 (IRF3) proteins were analyzed using Co-Immunoprecipitation (Co-IP) assay. In vivo assays were conducted by establishing HC subcutaneous xenograft tumor models. The study found a reduction in IFI16 expression in both HC tissues and DDP-resistant HC cell lines. The binding of IFI16 to IRF3 regulated DNA damage-associated markers in vitro. Overexpression of IFI16 heightened the susceptibility of DDP-induced apoptosis and DNA damage, which was counteracted by IRF3 knockdown, while strengthened by IRF3 overexpression. Moreover, overexpression of IFI16 diminished in vivo DDP-resistant HC tumorigenicity. In summary, our findings suggest that IFI16 serves as a tumor suppressor in HC by promoting DNA damage via its interaction with IRF3, thereby reversing DDP resistance.

Synbiotics improve growth performance and nutrient digestibility, inhibit PEDV infection, and prevent intestinal barrier dysfunction by mediating innate antivirus immune response in weaned piglets.

This experiment was conducted to explore the effects of dietary synbiotics (SYB) supplementation on growth performance, immune function, and intestinal barrier function in piglets challenged with porcine epidemic diarrhea virus (PEDV). Forty crossbred (Duroc × Landrace × Yorkshire) weaned piglets (26 ± 1d old) with a mean body weight (BW) of 6.62 ± 0.36kg were randomly allotted to five groups: control (CON) I and CONII group, both fed basal diet; 0.1% SYB group, 0.2% SYB group, and 0.2% yeast culture (YC) group, fed basal diet supplemented with 0.1%, 0.2% SYB, and 0.2% YC, respectively. On day 22, all piglets were orally administrated with 40mL PEDV (5.6 × 103 TCID50/mL) except piglets in CONI group, which were administrated with the same volume of sterile saline. The trial lasted for 26d. Before PEDV challenge, dietary 0.1% SYB supplementation increased final BW, average daily gain (ADG), and decreased the ratio of feed to gain during 0 to 21d (P < 0.05), as well as improved the apparent nutrient digestibility of dry matter (DM), organic matter (OM), crude protein, ether extract (EE), and gross energy (GE). At the same time, 0.2% YC also improved the apparent nutrient digestibility of DM, OM, EE, and GE (P < 0.05). PEDV challenge increased diarrhea rate and diarrhea indexes while decreased ADG (P < 0.05) from days 22 to 26, and induced systemic and intestinal mucosa innate immune and proinflammatory responses, destroyed intestinal barrier integrity. The decrease in average daily feed intake and ADG induced by PEDV challenge was suppressed by dietary SYB and YC supplementation, and 0.1% SYB had the best-alleviating effect. Dietary 0.1% SYB supplementation also increased serum interleukin (IL)-10, immunoglobulin M, complement component 4, and jejunal mucosal IL-4 levels, while decreased serum diamine oxidase activity compared with CONII group (P < 0.05). Furthermore, 0.1% SYB improved mRNA expressions of claudin-1, zonula occludens protein-1, mucin 2, interferon-γ, interferon regulatory factor-3, signal transducers and activators of transcription (P < 0.05), and protein expression of occludin, and downregulated mRNA expressions of toll-like receptor 3 and tumor necrosis factor-α (P < 0.05) in jejunal mucosa. Supplementing 0.2% SYB or 0.2% YC also had a positive effect on piglets, but the effect was not as good as 0.1% SYB. These results indicated that dietary 0.1% SYB supplementation improved growth performance under normal conditions, and alleviated the inflammatory response and the damage of intestinal barrier via improving innate immune function and decreasing PEDV genomic copies, showed optimal protective effects against PEDV infection.

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6-dependent STAT3 pathway.

Ulcerative colitis (UC) is an idiopathic chronic intestinal inflammation. An increasing body of evidence shows that macrophages play an important role in the pathogenesis of UC. Interferon regulatory factor 4 (IRF4) is crucial for the development of autoimmune diseases via regulating immune cells. This research was designed to explore the function of IRF4 in UC and its association with macrophage polarization. The in vitro model of UC was established by stimulating colonic epithelial cells with tumor necrosis factor α (TNF-α). A mouse model of UC was constructed by injecting C57BL/6 mice with dextran sulfate sodium salt. Flow cytometry was used to assess percentage of CD11b+ CD86+ and CD11b+ CD206+ cells in bone marrow macrophages. Occult blood tests were used to detect hematochezia. Hematoxylin and eosin staining assay was used to assess colon pathological changes. Enzyme-linked immunosorbent assay (ELISA) was used to detect concentrations of inflammatory cytokines. The interaction of IRF4 and B-cell lymphoma 6 (Bcl6) was confirmed using GST pull-down and coimmunoprecipitation assays. Our findings revealed that IRF4 promoted cell apoptosis and stimulated M1 macrophage polarization in vitro. Furthermore, IRF4 aggravated symptoms of the mouse model of UC and aggravated M1 macrophage polarization in vivo. IRF4 negatively regulated Bcl6 expression. Downregulation of Bcl6 promoted apoptosis and M1 macrophage polarization in the presence of IRF4 in vitro and in vivo. Moreover, Bcl6 positively mediated the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. In conclusion, IRF4 aggravated UC progression through promoting M1 macrophage polarization via Bcl6/JAK2/STAT3 pathway. These findings suggested that IRF4 might be a good target to competitively inhibit or to treat with UC.

Genome-wide analysis reveals the MORC3-mediated repression of PD-L1 expression in head and neck cancer.

Programmed death-ligand 1 (PD-L1) plays essential roles in the negative regulation of anti-tumor immunity. However, the regulatory mechanisms of PD-L1 expression need further exploration. MORC family CW-type zinc finger 3 (MORC3) is a transcriptional factor that regulates innate immune responses, but the expression and roles of MORC3 in cancers remain largely unknown. The present study explored the expression of MORC3 in cancers at both transcriptional and translational levels. The target genes and pathways were analyzed using RNA interference (RNAi), RNA sequencing (RNA-seq), and quantitative real-time polymerase chain reaction (qRT-PCR) technology in head and neck cancer cells. The expression of MORC3 and its target genes were also analyzed in single cancer cells. MORC3 was significantly downregulated in multiple cancers, including head and neck cancer, and low expression of MORC3 was associated with poor overall survival. MORC3 knockdown significantly increased the expression of many immune-related genes, including interferon (IFN)-associated genes [MX dynamin like GTPase 2 (MX2), interferon induced protein with tetratricopeptide repeats 1 (IFIT1), interferon induced protein with tetratricopeptide repeats 2 (IFIT2), interferon regulatory factor 7 (IRF7), interferon regulatory factor 9 (IRF9), interferon induced protein 44 like (IFI44L), interferon induced transmembrane protein 1 (IFITM1), interferon induced transmembrane protein 3 (IFITM3), interferon induced protein 44 (IFI44), and interferon induced with helicase C domain 1 (IFIH1)]. MORC3 knockdown significantly upregulated PD-L1 and signal transducer and activator of transcription 1 (STAT1) expression. Moreover, the LINC00880 immune-related long non-coding RNA (lnc-RNA) was upregulated by MORC3 knockdown. Silencing LINC00880 attenuated PD-L1 expression. MORC3 knockdown also increased the expression of cellular proliferation-related genes and promoted cancer cell proliferation. The present study demonstrated that MORC3 regulates IFN-associated pathways and is a novel repressor of PD-L1 expression and cancer cell proliferation.

Effectiveness of Narciclasine in Suppressing the Inflammatory Response in Sepsis: Molecular Docking and In Silico Studies.

Narciclasine is an alkaloid belonging to the Amaryllidaceae family which has been reported to have many beneficial properties. Especially its anticancer properties have been widely reported. Here, we have focused on its potential use in suppressing the inflammatory response in sepsis using in silico methods. Lipopolysaccharide (LPS) is an endotoxin which is present in the outer membrane of gram-negative bacteria and is a crucial player in the pathogenesis of gram-negative sepsis. Activation of toll-like receptor 4 (TLR4) signaling by LPS is an important event in the pathogenesis of gram-negative sepsis. This initiates a downstream signaling pathway comprising of several adaptor proteins such as toll/interleukin-1 receptor domain-containing adapter protein (TIRAP), myeloid differentiation primary response protein 88 (MyD88), interleukin-1 receptor-associated kinase (IRAK)-1, IRAK-4, interferon regulatory factor 3 (IRF-3), tumor necrosis factor receptor-associated factor 6 (TRAF-6) leading to nuclear factor kappa B (NF-κβ) activation resulting in elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. S100 calcium binding proteins A8/A9 (S100A8/A9) have been found to be an agonist of TLR4, and it amplifies the inflammatory response in sepsis. Molecular docking studies of narciclasine with target proteins associated with the LPS-TLR4 pathway showed that it has good binding affinity and stable interactions with the targets studied. Molecular dynamics (MD) simulation studies over 100 ns showed that most of the ligand-target complexes were stable. The structures of all the targets except TRAF-6 were retrieved from the Protein Data Bank (PDB) database. Homology modeling was done to predict the 3-dimensional structure of TRAF-6. MD simulation of narciclasine-TRAF-6 complex showed that the structure is stable. Metapocket was used for active site prediction in the target proteins. Toxicity analysis by admetSAR revealed that narciclasine was readily biodegradable and exhibited minimum toxicity. These results indicate that narciclasine has effective anti-inflammatory properties which could be useful in suppressing the inflammatory response in sepsis.

Nanocrystalline alloy-mediated delivery of mosaic epitope peptides for universal influenza vaccine.

Seasonal influenza infection poses great threat to public health systems. The flu vaccine remains the most effective method to reduce transmission and mortality. However, its effectiveness is limited due to the challenges in protecting against all influenza variants, as well as the weaker immune response observed in the adult population. Here, combining machine learning, synchrotron small angle X-ray scattering, we design an adjuvanted influenza vaccine composing mosaic epitope peptides selected from the hemagglutinin proteins of influenza A and B virus. These epitopes share similar physiochemical properties cognate to host antimicrobial peptides (AMPs) allowing them to form supramolecular assembly with poly(I:C), a synthetic toll-like receptor 3 (TLR3) agonist, through electrostatic interaction. The poly(I:C) is arranged into columnar lattice with the average inter-poly(I:C) distance commensurate with TLR3 and thereby capable of inducing multivalent TLR3 binding and hyperactivating the downstream inflammatory pathway. Interestingly, multiple AMP-like epitopes (Ampitopes) with compatible lattice parameter can co-crystalize into the same lattice to form 'alloy'-like composite with better poly(I:C) arrangement which allows the co-delivery of mosaic Ampitopes. The designed Ampitope-poly(I:C) nanocrystalline (and alloy) successfully activates interferon regulatory factor 3 (IRF3)-mediated pathway in antigen presenting cells. The intramuscular delivery of the nanocrystalline to the mice strongly trigger IL-6 and IFN-α release, which well-mimics the cytokines release pattern in influenza infected patients. After the third boost, the antigen-specific T cell response is 55 times higher compared to the free Ampitopes treatment group. Together, this vaccine offers a versatile way of eliciting strong and broad anti-flu protection.

Antiviral Effect of Extracellular Matrix Protein ABI3BP on Vesicular Stomatitis Virus and Its Mechanism: A Preliminary Study In Vitro

Objective To explore the influence of extracellular matrix protein ABI-interactor 3-binding protein (ABI3BP) on vesicular stomatitis virus (VSV) genome replication and innate immune signaling pathway.Methods The small interfering RNA (siRNA) was transfected to knock down ABI3BP gene in human skin fibroblast BJ-5ta cells. VSV-green fluorescent protein (VSV-GFP)-infected cell model was established. The morphological changes and F-actin stress fiber formation were detected on ABI3BP knockdown cells by phalloidin immunofluorescence staining. The mRNA level of virus replication was detected by RT-qPCR in BJ-5ta cells after VSV-GFP infection; western blotting was performed to detect the changes in interferon regulatory factor 3 (IRF3) and TANK-binding kinase 1 (TBK1) phosphorylation levels.Results The VSV-GFP-infected BJ-5ta cell model was successfully established. Efficient knockdown of ABI3BP in BJ-5ta cells was achieved. Phalloidin immunofluorescence staining revealed structural rearrangement of intracellular F-actin after ABI3BP gene knockdown. Compared with the control group, the gene copy number of VSV-GFP in ABI3BP knockdown cells increased by 2.2 - 3.5 times (P<0.01) and 2.2 - 4.0 times (P<0.01) respectively when infected with VSV of multiplicity of infection 0.1 and 1. The expression of viral protein significantly increased in ABI3BP knockdown cells after virus infection. The activation of type-I interferon pathway, as determined by phosphorylated IRF3 and phosphorylated TBK1, was significantly decreased in ABI3BP knockdown cells after VSV-GFP infection.Conclusions Extracellular matrix protein ABI3BP plays an important role in maintaining the formation and rearrangement of actin structure. ABI3BP gene deletion promotes RNA virus replication, and ABI3BP is an important molecule that maintains the integrity of type I interferon pathway.

Sebacic acid, a royal jelly-containing fatty acid, decreases LPS-induced IL-6 mRNA expression in differentiated human THP-1 macrophage-like cells.

Macrophages produce many inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in innate immune responses. However, excess production of these mediators by activated macrophages triggers deleterious effects, leading to disorders associated with inflammation. Royal jelly (RJ), a milky-white substance secreted by worker bees, contains unique fatty acids, including 10-hydroxy-2-decenoic acid (10H2DA) and sebacic acid (SA). 10H2DA has been reported to have various biological functions, such as anti-inflammation. However, the anti-inflammatory effect of SA is not fully understood. In this study, we investigated the effects of SA on lipopolysaccharide (LPS)-induced cytokine expression using differentiated human THP-1 macrophage-like cells. SA dose-dependently decreased LPS-induced mRNA expression of IL-6, but not TNF-α and IL-1β. SA suppressed the phosphorylation of signal transducers and activators of transcription 1 (STAT1) and STAT3, but hardly affected the activation of JNK, p38, or NF-κB. In addition, SA decreased LPS-induced interferon-β (IFN-β) expression, and the addition of IFN-β restored the inhibition by SA of LPS-induced STAT activation and IL-6 expression. Furthermore, SA suppressed LPS-induced nuclear translocation of interferon regulatory factor 3 (IRF3), a transcription factor responsible for IFN-β expression. Taken together, we conclude that SA selectively decreases LPS-induced expression of IL-6 mRNA through inhibition of the IRF3/IFN-β/STAT axis.

Salvia miltiorrhiza bge. f. alba ameliorates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease via the STING pathway.

To elucidate the functional role and underlying mechanism of Salvia miltiorrhiza bge. f. alba (SMBFA) in patients with type 2 diabetes mellitus (T2DM) accompanied by non-alcoholic fatty liver disease (NAFLD). A retrospective analysis was conducted on 90 patients with T2DM-NAFLD who met the inclusion criteria. The control group was comprised of 45 patients treated with Fenofibrate, while the observation group consisted of 45 patients who received SMBFA in addition to the control treatment. An in vivo mouse model of T2DM-NAFLD was established using a high-fat diet combined with streptozotocin. Serum levels of fasting plasma glucose (FPG), 2-hour postprandial glucose (2h PG), hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), and triglyceride (TG) were measured in both patients and mice using an automated biochemical analyzer. Liver indices and function were also evaluated. ELISA assays were performed to quantify inflammatory cytokine levels. Western blotting was utilized to assess the protein levels related to the stimulator of interferon genes (STING)-interferon regulatory factor 3 (IRF3) pathway. After treatment, significant reductions in blood glucose indices, HOMA-IR, lipid metabolism markers, liver function indices, and inflammatory cytokines were observed in both groups of T2DM-NAFLD patients. Notably, the decreases were more pronounced in the observation group compared to the control group. Similarly, in T2DM-NAFLD mouse models, the levels of these parameters were significantly lower in the observation group than in the normal control (NC) group. Additionally, SMBFA suppressed the elevated levels of STING, p-IRF3, and p-TANK-binding kinase 1 in the T2DM-NAFLD mice. SMBFA exhibits the potential to regulate glucose and lipid metabolism, inhibit insulin resistance, and protect liver function by modulating the STING signaling pathway.

Case report and functional verification of a novel mutation in the interferon regulatory transcription factor 6 gene in a family with orofacial clefts.

This study aimed to identify the causative genetic variant in a Chinese family with orofacial clefts. We retrospectively analyzed the clinical information of a family with orofacial clefts. Then, we performed an etiological genetic analysis of the family using whole exome sequencing analysis and Sanger sequencing. We created a hybrid code-shifting mutation cell line (293T-462het) and evaluated its impact on cell proliferation, migration, and apoptosis, as well as E-cadherin and vimentin expression. Whole exome sequencing revealed a novel heterozygous variant c.1386del (p.A462Pfs*28) in the interferon regulatory transcription factor 6 (IRF6) gene in a family with orofacial clefts. Sanger sequencing further confirmed that this heterozygous variant was the genetic cause of orofacial clefts in this family. The c.1386del variant of IRF6 was classified as likely pathogenic. The heterozygous mutation IRF6 (c.1386del) enhanced cell proliferation and migration while inhibiting cell apoptosis and regulating the expression of E-cadherin and vimentin. This study identified a novel c.1386del mutation in the IRF6 gene and explored how this mutation leads to lip and palate defects. Our results provide a solid theoretical foundation for future genetic detection of these orofacial defects.

A gold nanocluster/MIL-100(Fe) bimodal nanovector for the therapy of inflammatory disease through attenuation of Toll-like receptor signaling.

A better understanding of the molecular and cellular events involved in the inflammation process has opened novel perspectives in the treatment of inflammatory diseases, particularly through the development of well-designed nanomedicines. Here we describe the design of a novel class of anti-inflammatory nanomedicine (denoted as Au@MIL) synthesized through a one-pot, cost-effective and green approach by coupling a benchmark mesoporous iron(III) carboxylate metal organic framework (MOF) (i.e. MIL-100(Fe)) and glutathionate protected gold nanoclusters (i.e. Au25SG18 NCs). This nano-carrier exhibits low toxicity and excellent colloidal stability combined with the high loading capacity of the glucocorticoid dexamethasone phosphate (DexP) whose pH-dependent delivery was observed. The drug loaded Au@MIL nanocarrier shows high anti-inflammatory activity due to its capacity to specifically hinder inflammatory cell growth, scavenge intracellular reactive oxygen species (ROS) and downregulate pro-inflammatory cytokine secretion. In addition, this formulation has the capacity to inhibit the Toll-like receptor (TLR) signaling cascade namely the nuclear factor kappa B (NF-κB) and the interferon regulatory factor (IRF) pathways. This not only provides a new avenue for the nanotherapy of inflammatory diseases but also enhances our fundamental knowledge of the role of nanoMOF based nanomedicine in the regulation of innate immune signaling.

ITLN1, regulated by interferon regulatory factor 1, suppresses HCC proliferation via activation of ERK1/2 signaling

ITLN1, regulated by interferon regulatory factor 1, suppresses HCC proliferation via activation of ERK1/2 signaling

Identification of potential therapeutic targets for multiple myeloma by gene expression analysis

New treatments are needed for multiple myeloma (MM), an almost always incurable cancer of plasma cells. Cancer therapies might have fewer side effects if they are aimed at specific protein targets expressed by cancer cells. We hypothesized that differences in gene expression between multiple myeloma cells and normal cells could be used to identify new targets for MM therapies. RNA sequencing (RNAseq) is a technique for quantifying gene expression in cells. We analyzed RNAseq data from the Cancer Cell Line Encyclopedia to identify genes with high expression in MM cell lines versus cell lines derived from cancers other than MM. Next, the 200 genes with the highest expression in MM cell lines versus other cell lines were evaluated for RNA expression in primary MM samples from patients. Of these genes, 72 were expressed in at least 23 of 25 primary samples from patients. We evaluated the 72 genes expressed at high levels in MM cell lines and expressed in primary MM cells for expression in normal human tissues. We evaluated gene expression in normal human tissues by using publicly available RNAseq data. Genes with high expression in normal tissues were eliminated as potential targets to decrease the chance of side effects caused by therapies targeting proteins expressed by normal tissues. We identified 19 genes with high expression in MM and low expression in normal tissues. The proteins encoded by these genes are promising therapeutic targets for MM and include Prepronociceptin (PNOC) and Interferon Regulatory Factor 4 (IRF4).

Transcriptomic response of lumpfish (Cyclopterus lumpus) head kidney to viral mimic, with a focus on the interferon regulatory factor family.

The economic importance of lumpfish (Cyclopterus lumpus) is increasing, but several aspects of its immune responses are not well understood. To discover genes and mechanisms involved in the lumpfish antiviral response, fish were intraperitoneally injected with either the viral mimic polyinosinic:polycytidylic acid [poly(I:C)] or phosphate-buffered saline (PBS; vehicle control), and head kidneys were sampled 24 hours post-injection (hpi) for transcriptomic analyses. RNA sequencing (RNA-Seq) (adjusted p-value <0.05) identified 4,499 upregulated and 3,952 downregulated transcripts in the poly(I:C)-injected fish compared to the PBS-injected fish. Eighteen genes identified as differentially expressed by RNA-Seq were included in a qPCR study that confirmed the upregulation of genes encoding proteins with antiviral immune response functions (e.g., rsad2) and the downregulation of genes (e.g., jarid2b) with potential cellular process functions. In addition, transcript expression levels of 12 members of the interferon regulatory factor (IRF) family [seven of which were identified as poly(I:C)-responsive in this RNA-Seq study] were analyzed using qPCR. Levels of irf1a, irf1b, irf2, irf3, irf4b, irf7, irf8, irf9, and irf10 were significantly higher and levels of irf4a and irf5 were significantly lower in the poly(I:C)-injected fish compared to the PBS-injected fish. This research and associated new genomic resources enhance our understanding of the genes and molecular mechanisms underlying the lumpfish response to viral mimic stimulation and help identify possible therapeutic targets and biomarkers for viral infections in this species.

Anchorage Dependence and Cancer Metastasis.

The process of cancer metastasis is dependent on the cancer cells' capacity to detach from the primary tumor, endure in a suspended state, and establish colonies in other locations. Anchorage dependence, which refers to the cells' reliance on attachment to the extracellular matrix (ECM), is a critical determinant of cellular shape, dynamics, behavior, and, ultimately, cell fate in nonmalignant and cancer cells. Anchorage-independent growth is a characteristic feature of cells resistant to anoikis, a programmed cell death process triggered by detachment from the ECM. This ability to grow and survive without attachment to a substrate is a crucial stage in the progression of metastasis. The recently discovered phenomenon named "adherent-to-suspension transition (AST)" alters the requirement for anchoring and enhances survival in a suspended state. AST is controlled by four transcription factors (IKAROS family zinc finger 1, nuclear factor erythroid 2, BTG anti-proliferation factor 2, and interferon regulatory factor 8) and can detach cells without undergoing the typical epithelial-mesenchymal transition. Notably, AST factors are highly expressed in circulating tumor cells compared to their attached counterparts, indicating their crucial role in the spread of cancer. Crucially, the suppression of AST substantially reduces metastasis while sparing primary tumors. These findings open up possibilities for developing targeted therapies that inhibit metastasis and emphasize the importance of AST, leading to a fundamental change in our comprehension of how cancer spreads.

Influence of Metformin in Malignant Development of Liver Cancer Cells through Interferon Regulatory Factor 1

Influence of Metformin in Malignant Development of Liver Cancer Cells through Interferon Regulatory Factor 1

Adipose Tissue Macrophages.

In obesity, adipose tissue macrophages (ATMs) are abundant immune cells in the adipose tissue and are known as inducers of metabolic inflammation that may lead to insulin resistance and immune disorders associated with obesity. However, much less is known about the ontogeny and physiological functions of ATMs in lean adipose tissue. ATMs are present at birth and actively participate in the synthesis of mediators that induce lipolysis, mitobiogenesis, and thermogenesis in adipocytes. Later in life ATMs limit the thermogenic competence of the adipocytes and favor lipid storage. ATMs respond to lipid overload of adipocytes in obesity with a sequence of pro-inflammatory events, including inflammasome activation and pyroptosis, as well as stimulation of nuclear factor kappa B and interferon regulatory factors that evoke an uncontrolled inflammation. ATMs are life-long constituents of the adipose tissue and hence signals that control ATM development and ATM-adipocyte interactions determine adipose tissue health.

Interferon-gamma regulates the progression of neuroblastoma cells through interferon-regulatory factor-1

Interferon-gamma regulates the progression of neuroblastoma cells through interferon-regulatory factor-1