Psoriasis is a chronic non-contagious autoimmune disease. Gallic acid is a natural compound with potential health benefits, including antioxidant, anticancer, antiviral and antibacterial properties. Nevertheless, the influence of gallic acid on psoriasis has not been fully determined. This investigation aimed to discover the effect of gallic acid on psoriasis. Thirty-one pairs of psoriatic skin tissues and healthy adult human skin tissues were collected. Human keratinocytes (HaCaT cells) were transfected with interleukin 17A (IL-17A) to create the psoriatic keratinocyte model. The content of bromodomain-containing protein 4 (BRD4) microRNA was assessed using qRT-PCR testing. The content of BRD4 was detected by Western blotting. Cell migration was evaluated by conducting a wound healing assay. Cell proliferation was determined using an EdU assay. Apoptosis was detected by the TUNEL assay. The contents of interferon gamma (IFN-γ), IL-6, IL-8 and IL-17 were detected by ELISA. BRD4 was up-regulated in psoriatic skin tissues and in the IL-17A group compared to the healthy adult human skin tissues and the control group. Silencing BRD4 inhibited cell migration, proliferation and inflammatory response but induced apoptosis in IL-17A-treated HaCaT cells. Conversely, BRD4 over-expression promoted cell migration, proliferation and inflammatory response but suppressed apoptosis in IL-17A-treated HaCaT cells. Gallic acid repressed cell migration, proliferation and inflammatory response but indu-ced apoptosis in HaCaT cells transfected with IL-17A by down-regulating BRD4. Gallic acid represses cell migration, proliferation and inflammatory response but induces apoptosis in IL-17A-transfected HaCaT cells by down-regulating BRD4.

• MeSH
• Apoptosis * drug effects   MeSH
• HaCaT Cells MeSH
• Cell Line MeSH
• Adult MeSH
• Interleukin-17 metabolism   MeSH
• Nuclear Proteins metabolism   genetics   MeSH
• Keratinocytes * drug effects   metabolism   MeSH
• Gallic Acid * pharmacology   MeSH
• Humans MeSH
• MicroRNAs genetics   metabolism   MeSH
• Cell Movement * drug effects   MeSH
• Cell Proliferation * drug effects   MeSH
• Cell Cycle Proteins * metabolism   genetics   MeSH
• Bromodomain Containing Proteins MeSH
• Psoriasis * metabolism   pathology   drug therapy   MeSH
• Gene Expression Regulation drug effects   MeSH
• Transcription Factors * metabolism   MeSH
• Inflammation * pathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

• MeSH
• Gain of Function Mutation MeSH
• Autoantibodies * immunology   MeSH
• COVID-19 genetics   immunology   MeSH
• Thyroid Epithelial Cells metabolism   pathology   MeSH
• Genetic Predisposition to Disease * MeSH
• Heterozygote MeSH
• Interferon Type I * antagonists & inhibitors   immunology   MeSH
• NF-kappaB-Inducing Kinase MeSH
• Humans MeSH
• Loss of Function Mutation MeSH
• NF-kappa B p52 Subunit deficiency   genetics   MeSH
• NF-kappa B * deficiency   genetics   MeSH
• AIRE Protein MeSH
• I-kappa B Proteins deficiency   genetics   MeSH
• Thymus Gland abnormalities   immunology   pathology   MeSH
• Pneumonia, Viral genetics   immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Gene inactivation of the cyclin-dependent kinase inhibitors p16INK4a, p15INK4b and p21WAF is frequently mediated by promoter gene methylation, whereas histone deacetylases (HDACs) control gene expression through their ability to deacetylate proteins. The effect of suberohydroxamic acid (SBHA) and 5-Aza-2'-deoxycytidine (Decitabine) (DAC) treatments on the transcription of CDKN2A, CDKN2B and CDKN1A genes, and their effects on molecular biological behavior were examined in two myeloma cell lines, RPMI8226 and U266, which differ in p53-functionality and IL-6 expression. In both tested myeloma cell lines, a non-methylated state of the CDKN2B gene promoter region was detected with normal gene expression, and the same level of p15INK4b protein was detected by immunocytochemical staining. Furthermore, in myeloma cells treated with SBHA and DAC alone, the expression of both p15INK4b and p21WAF was significantly upregulated in RPMI8226 cells (p53-functional, without IL-6 expression), whereas in the U266 cell line (p53 deleted, expressing IL-6) only p21WAF expression was significantly increased. Moreover, the analysis revealed that treatment with DAC induced DNMT3B enhancement in U266 cells. In conclusion, in myeloma cells with IL-6 expression, significantly increased DNMT3B expression indicated the tumorigenic consequences of 5-Aza-2'deoxycytidine treatment, which requires careful use in diseases involving epigenetic dysregulation, such as multiple myeloma (MM).

• MeSH
• Decitabine * pharmacology   MeSH
• DNA (Cytosine-5-)-Methyltransferases * genetics   metabolism   MeSH
• Epigenesis, Genetic * MeSH
• Cyclin-Dependent Kinase Inhibitor p15 genetics   metabolism   MeSH
• Cyclin-Dependent Kinase Inhibitor p16 genetics   metabolism   MeSH
• Interleukin-6 genetics   metabolism   MeSH
• Humans MeSH
• DNA Methylation MeSH
• Multiple Myeloma * genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Cell Cycle Proteins genetics   metabolism   MeSH
• Gene Silencing MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream-effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34+ /CD38- leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22T315I . The BRD4-targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1-resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast-induced TKI resistance of CML LSC in a co-culture system and to block interferon-gamma-induced upregulation of the checkpoint antigen PD-L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.

• MeSH
• Fusion Proteins, bcr-abl MeSH
• Blast Crisis drug therapy   MeSH
• Drug Resistance, Neoplasm MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   genetics   metabolism   MeSH
• Protein Kinase Inhibitors pharmacology   therapeutic use   MeSH
• Nuclear Proteins * genetics   MeSH
• Stem Cells MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Cell Cycle Proteins MeSH
• Proto-Oncogene Proteins c-myc MeSH
• Transcription Factors genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Vaccinia virus (VACV) is an enveloped DNA virus from the Orthopoxvirus family, various strains of which were used in the successful eradication campaign against smallpox. Both original and newer VACV-based replicating vaccines reveal a risk of serious complications in atopic individuals. VACV encodes various factors interfering with host immune responses at multiple levels. In atopic skin, the production of type I interferon is compromised, while VACV specifically inhibits the phosphorylation of the Interferon Regulatory Factor 3 (IRF-3) and expression of interferons. To overcome this block, we generated a recombinant VACV-expressing murine IRF-3 (WR-IRF3) and characterized its effects on virus growth, cytokine expression and apoptosis in tissue cultures and in spontaneously atopic Nc/Nga and control Balb/c mice. Further, we explored the induction of protective immune responses against a lethal dose of wild-type WR, the surrogate of smallpox. We demonstrate that the overexpression of IRF-3 by WR-IRF3 increases the expression of type I interferon, modulates the expression of several cytokines and induces superior protective immune responses against a lethal poxvirus challenge in both Nc/Nga and Balb/c mice. Additionally, the results may be informative for design of other virus-based vaccines or for therapy of different viral infections.

• MeSH
• Gene Expression genetics   MeSH
• Immunity immunology   MeSH
• Poxviridae Infections immunology   prevention & control   MeSH
• Interferon Type I metabolism   MeSH
• Interferon Regulatory Factor-3 genetics   immunology   MeSH
• Interleukin-1beta immunology   MeSH
• Skin immunology   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Poxviridae pathogenicity   MeSH
• Gene Expression Regulation, Viral genetics   MeSH
• Virus Replication immunology   MeSH
• Vaccinia virology   MeSH
• Viral Vaccines immunology   MeSH
• Vaccinia virus genetics   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The mechanism by which DNA viruses interact with different DNA sensors and their connection with the activation of interferon (IFN) type I pathway are poorly understood. We investigated the roles of protein 204 (p204) and cyclic guanosine-adenosine synthetase (cGAS) sensors during infection with mouse polyomavirus (MPyV). The phosphorylation of IFN regulatory factor 3 (IRF3) and the stimulator of IFN genes (STING) proteins and the upregulation of IFN beta (IFN-β) and MX Dynamin Like GTPase 1 (MX-1) genes were detected at the time of replication of MPyV genomes in the nucleus. STING knockout abolished the IFN response. Infection with a mutant virus that exhibits defective nuclear entry via nucleopores and that accumulates in the cytoplasm confirmed that replication of viral genomes in the nucleus is required for IFN induction. The importance of both DNA sensors, p204 and cGAS, in MPyV-induced IFN response was demonstrated by downregulation of the IFN pathway observed in p204-knockdown and cGAS-knockout cells. Confocal microscopy revealed the colocalization of p204 with MPyV genomes in the nucleus. cGAS was found in the cytoplasm, colocalizing with viral DNA leaked from the nucleus and with DNA within micronucleus-like bodies, but also with the MPyV genomes in the nucleus. However, 2'3'-Cyclic guanosine monophosphate-adenosine monophosphate synthesized by cGAS was detected exclusively in the cytoplasm. Biochemical assays revealed no evidence of functional interaction between cGAS and p204 in the nucleus. Our results provide evidence for the complex interactions of MPyV and DNA sensors including the sensing of viral genomes in the nucleus by p204 and of leaked viral DNA and micronucleus-like bodies in the cytoplasm by cGAS.

• MeSH
• DNA, Viral genetics   immunology   MeSH
• Phosphoproteins antagonists & inhibitors   genetics   metabolism   MeSH
• Phosphorylation MeSH
• Tumor Virus Infections immunology   virology   MeSH
• Host-Pathogen Interactions MeSH
• Interferon-beta metabolism   MeSH
• Nuclear Proteins antagonists & inhibitors   genetics   metabolism   MeSH
• Membrane Proteins antagonists & inhibitors   genetics   metabolism   MeSH
• Mice MeSH
• Nucleotidyltransferases antagonists & inhibitors   genetics   metabolism   MeSH
• Polyomavirus Infections immunology   virology   MeSH
• Polyomavirus genetics   immunology   MeSH
• Immunity, Innate immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Interferon (IFN)-related DNA damage resistant signature (IRDS) genes are a subgroup of interferon-stimulated genes (ISGs) found upregulated in different cancer types, which promotes resistance to DNA damaging chemotherapy and radiotherapy. Along with briefly discussing IFNs and signalling in this review, we highlighted how different IRDS genes are affected by viruses. On the contrary, different strategies adopted to suppress a set of IRDS genes (STAT1, IRF7, OAS family, and BST2) to induce (chemo- and radiotherapy) sensitivity were deliberated. Significant biological pathways that comprise these genes were classified, along with their frequently associated genes (IFIT1/3, IFITM1, IRF7, ISG15, MX1/2 and OAS1/3/L). Major upstream regulators from the IRDS genes were identified, and different IFN types regulating these genes were outlined. Functional interfaces of IRDS proteins with DNA/RNA/ATP/GTP/NADP biomolecules featured a well-defined pharmacophore model for STAT1/IRF7-dsDNA and OAS1/OAS3/IFIH1-dsRNA complexes, as well as for the genes binding to GDP or NADP+. The Lys amino acid was found commonly interacting with the ATP phosphate group from OAS1/EIF2AK2/IFIH1 genes. Considering the premise that targeting IRDS genes mediated resistance offers an efficient strategy to resensitize tumour cells and enhances the outcome of anti-cancer treatment, this review can add some novel insights to the field.

• MeSH
• Adaptor Proteins, Signal Transducing physiology   MeSH
• Transcriptional Activation MeSH
• Drug Resistance, Neoplasm genetics   physiology   MeSH
• RNA, Double-Stranded MeSH
• Interferon Regulatory Factor-7 MeSH
• Interferons metabolism   physiology   MeSH
• Intracellular Signaling Peptides and Proteins MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• DNA Damage genetics   physiology   MeSH
• RNA-Binding Proteins MeSH
• Signal Transduction MeSH
• STAT1 Transcription Factor MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Lambda interferons mediate antiviral immunity by inducing interferon-stimulated genes (ISGs) in epithelial tissues. A common variant rs368234815TT/∆G creating functional gene from an IFNL4 pseudogene is associated with the expression of major ISGs in the liver but impaired clearance of hepatitis C. To explain this, we compared Halo-tagged and non-tagged IFNL3 and IFNL4 signaling in liver-derived cell lines. Transfection with non-tagged IFNL3, non-tagged IFNL4 and Halo-tagged IFNL4 led to a similar degree of JAK-STAT activation and ISG induction; however, the response to transfection with Halo-tagged IFNL3 was lower and delayed. Transfection with non-tagged IFNL3 or IFNL4 induced no transcriptome change in the cells lacking either IL10R2 or IFNLR1 receptor subunits. Cytosolic overexpression of signal peptide-lacking IFNL3 or IFNL4 in wild type cells did not interfere with JAK-STAT signaling triggered by interferons in the medium. Finally, expression profile changes induced by transfection with non-tagged IFNL3 and IFNL4 were highly similar. These data do not support the hypothesis about IFNL4-specific non-canonical signaling and point out that functional studies conducted with tagged interferons should be interpreted with caution.

• MeSH
• Cell Line MeSH
• Hep G2 Cells MeSH
• Gene Expression MeSH
• Gene Knockout Techniques MeSH
• Hepatocytes immunology   metabolism   MeSH
• Interferon Regulatory Factors genetics   metabolism   MeSH
• Interferons deficiency   genetics   metabolism   MeSH
• Interleukins deficiency   genetics   metabolism   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Interleukin-10 Receptor beta Subunit deficiency   genetics   metabolism   MeSH
• Receptors, Interferon deficiency   genetics   metabolism   MeSH
• Recombinant Proteins genetics   metabolism   MeSH
• Signal Transduction MeSH
• Transfection MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Plasmacytoid dendritic cells (pDCs) are the most potent type I interferon-producing cells and play an important role in antiviral immunity. Tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce interferon alpha (IFNα) and confirmed capacity to prime regulatory T cells (Tregs) by the ICOS/ICOS-L pathway. Because a significant number of HNSCCs are induced by human papillomaviruses and show markedly different immune profiles than non-virally induced tumors, we compared the phenotype and functional capacity of HNSCC-infiltrating pDCs to the HPV status of the tumor. We observed a reduced capacity of pDCs to produce IFNα upon toll-like receptor activation in HPV-negative samples and a rather uncompromised functionality in HPV-associated tumors. Additionally, supernatants from non-virally induced but not HPV-associated tumor cell suspensions significantly inhibited IFNα production by peripheral blood-derived pDCs. We identified IL-10 and TNFα as the soluble pDC-suppressive factors with the highest variability between HPV-negative and HPV-positive tumor-derived supernatants. Additionally, we observed a positive correlation of tumor-infiltrating pDCs with Tregs in HPV-negative samples but not in virally induced tumors. Overall, our study indicates that the immunosuppressive cytokine milieu rich in IL-10 and TNFα in HPV-negative but not in HPV-positive HNSCC significantly affects the functional capacity of tumor-infiltrating pDCs, and such dysfunctional pDCs may further support the immunosuppressive tumor microenvironment by promoting the expansion of Tregs in the tumor tissue.

• MeSH
• Biomarkers MeSH
• Cytokines metabolism   MeSH
• Dendritic Cells immunology   metabolism   pathology   MeSH
• Squamous Cell Carcinoma of Head and Neck etiology   metabolism   pathology   MeSH
• Gene Expression MeSH
• Papillomavirus Infections complications   virology   MeSH
• Interferon-alpha immunology   metabolism   MeSH
• Humans MeSH
• Disease Susceptibility MeSH
• Tumor Microenvironment * immunology   MeSH
• T-Lymphocytes, Regulatory immunology   metabolism   MeSH
• Case-Control Studies MeSH
• T-Lymphocyte Subsets immunology   metabolism   MeSH
• Cell Transformation, Viral MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The knowledge of mechanisms of regulation of IL-10 production by B cells remains still very limited. We show here that highly purified mouse B cells stimulated with LPS produce significant levels of IL-10, but Bregs in our model do not express detectable level of either Foxp3 or GATA-3. Nevertheless, IL-10 production by B cells is regulated by cytokines. In activated B cells, IL-10 production was significantly enhanced by IFN-γ and decreased in the presence of IL-4 or TGF-β. These findings are in sharp contrast with the observations in T cells, where IL-10 production correlates with GATA-3 or FoxP3 expression, and the cytokines regulate IL-10 production in a reverse manner than in activated B cells. These results thus show that the production of IL-10 by Bregs is regulated by cytokines independently of the expression of GATA-3 and FoxP3, which is clearly different from GATA-3-dependent IL-10 production by activated Th2 cells and FoxP3 expression in IL-10-producing Tregs.

• MeSH
• Lymphocyte Activation immunology   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit immunology   MeSH
• Forkhead Transcription Factors metabolism   MeSH
• Interferon-gamma immunology   MeSH
• Interleukin-10 biosynthesis   MeSH
• Interleukin-4 immunology   MeSH
• Cells, Cultured MeSH
• Lipopolysaccharides immunology   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• B-Lymphocytes, Regulatory immunology   MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Th2 Cells immunology   MeSH
• Transforming Growth Factor beta immunology   MeSH
• GATA3 Transcription Factor metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH