Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN-inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti-IFNAR or anti-IFN-α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA-binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti-IFNAR or anti-IFN-α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA-binding proteins and with autoantibody multispecificity. These studies identify IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN-α as a possible target for therapy in these patients.

• MeSH
• autoprotilátky imunologie   MeSH
• dermatomyozitida imunologie   MeSH
• interferon typ I metabolismus   MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• myozitida s inkluzními tělísky imunologie   MeSH
• prospektivní studie MeSH
• proteiny vázající RNA imunologie   MeSH
• senioři MeSH
• signální transdukce MeSH
• specificita protilátek * MeSH
• systémový lupus erythematodes imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• autoprotilátky MeSH
• interferon typ I MeSH
• proteiny vázající RNA MeSH

The signal transducers and transcription activators (STATs) and their endogenous inhibitors of the suppressors of cytokine signalling (SOCS) family are major proteins harmonizing the transmission of external signals from the surface membrane to target genes in the nucleus. To correlate the induction of SOCS 3 by interferons (IFNs) on messenger RNA and protein levels with STAT 1 phosphorylation in human malignant melanoma cell lines, we used a unique collection of 18 established malignant melanoma cell lines and six human non-malignant normal cells (two melanocytes, two skin keratinocytes and two fibroblasts). IFN-gamma induced SOCS 3 in 83% of melanoma cell lines, whereas IFN-alpha stimulated SOCS 3 expression in only 11% of cases. Similarly, melanocytes showed strong induction of SOCS 3 by IFN-gamma and, to a lesser extent, by IFN-alpha. In most cases, SOCS 3 expression was paralleled by STAT 1 phosphorylation at tyrosine residues (Y701). In several lines, however, SOCS 3 was not induced despite STAT 1 phosphorylation and, in a few lines, SOCS 3 induction occurred without detectable STAT 1 phosphorylation, indicating that STAT 1 might not be an exclusive inducer of SOCS 3. Similarly, non-malignant cells displayed STAT 1 activation and high levels of SOCS 3 expression after IFN-gamma (but not IFN-alpha) treatment. In conclusion, in contrast to IFN-alpha, IFN-gamma appeared to induce SOCS 3 apparently at the transcription level and exhibited higher cytotoxic effects regardless of the cell origin.

• MeSH
• buňky - růstové procesy účinky léků   MeSH
• fosforylace MeSH
• interferon gama farmakologie   MeSH
• interferon typ I farmakologie   MeSH
• lidé MeSH
• melanom farmakoterapie   genetika   metabolismus   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• nádorové buněčné linie MeSH
• northern blotting MeSH
• protein SOCS3 MeSH
• proteiny SOCS biosyntéza   genetika   MeSH
• rekombinantní proteiny MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 metabolismus   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferon gama MeSH
• interferon typ I MeSH
• messenger RNA MeSH
• protein SOCS3 MeSH
• proteiny SOCS MeSH
• rekombinantní proteiny MeSH
• SOCS3 protein, human MeSH Prohlížeč
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

We hereby describe the process of design and selection of nonantibody protein binders mimicking cytokine signaling. We chose to mimic signaling of IFN-λ1, type 3 interferon (also known as IL-29) for its novelty and the importance of its biological functions. All four known interferons λ signal through binding to the extracellular domains of IL-28 receptor 1 (IL-28R1) and IL-10 receptor 2 (IL-10R2). Our binders were therefore trained to bind both receptors simultaneously. The bifunctional binder molecules were developed by yeast display, a method of directed evolution. The signaling capacity of the bivalent binders was tested by measuring phosphorylation of the JAK/STAT signaling pathway and production of mRNA of six selected genes naturally induced by IFN- λ1 in human cell lines. The newly developed bivalent binders offer opportunities to study cytokine-related biological functions and modulation of the cell behavior by receptor activation on the cell surfaces alternative to the use of natural IFN-λ.

• Klíčová slova
• IFN-λ, IL-29, cytokine signaling, cytokines, directed evolution, interferon lambda, protein scaffolds, yeast display,
• MeSH
• antivirové látky metabolismus   MeSH
• cytokiny metabolismus   MeSH
• interferony * metabolismus   MeSH
• interleukiny * metabolismus   MeSH
• lidé MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• cytokiny MeSH
• interferony * MeSH
• interleukiny * MeSH

IFN-γ is a pleiotropic cytokine crucial for both innate and adaptive immunity, which also plays a critical role in immunological surveillance of cancer. Genetic defects or gene silencing in the IFN-γ signal transduction pathways as well as in the expression of IFN-γ-regulated genes represent frequent mechanisms by which tumour cells can escape from immune responses. Epigenetic control of the IFN-γ signalling pathway activation associated with epigenetic changes in the corresponding regulatory gene regions, such as chromatin remodelling, histone acetylation and methylation, and DNA demethylation is frequently dysregulated in tumour cells. Epigenetic silencing of the IFN-γ regulatory pathway components, as well as of the IFN-γ-regulated genes crucial for tumour cell recognition or induction of anti-tumour immune responses, has been documented in various cancer models. Expression of both IFN-γ signalling pathway components and selected IFN-γ-regulated genes can be influenced by epigenetic modifiers, namely DNA methyltransferase and histone deacetylase inhibitors. These agents thus can mimic, restore, or boost the immunomodulatory effects of IFN-γ in tumour cells, which can contribute to their anti-tumour therapeutic efficacies and justifies their potential use in combined epigenetic therapy with immunotherapeutic approaches.

• MeSH
• epigeneze genetická * MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• metylace DNA genetika   MeSH
• nádory genetika   metabolismus   MeSH
• restrukturace chromatinu MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• interferon gama MeSH

Interferon (IFN) signaling has been suggested to play an important role in colorectal carcinogenesis. Our study aimed to examine potentially functional genetic variants in interferon regulatory factor 3 (IRF3), IRF5, IRF7, type I and type II IFN and their receptor genes with respect to colorectal cancer (CRC) risk and clinical outcome. Altogether 74 single nucleotide polymorphisms (SNPs) were covered by the 34 SNPs genotyped in a hospital-based case-control study of 1327 CRC cases and 758 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall survival and event-free survival in a subgroup of 483 patients. Seven SNPs in IFNA1, IFNA13, IFNA21, IFNK, IFNAR1 and IFNGR1 were associated with CRC risk. After multiple testing correction, the associations with the SNPs rs2856968 (IFNAR1) and rs2234711 (IFNGR1) remained formally significant (P = 0.0015 and P<0.0001, respectively). Multivariable survival analyses showed that the SNP rs6475526 (IFNA7/IFNA14) was associated with overall survival of the patients (P = 0.041 and event-free survival among patients without distant metastasis at the time of diagnosis, P = 0.034). The hazard ratios (HRs) for rs6475526 remained statistically significant even after adjustment for age, gender, grade and stage (P = 0.029 and P = 0.036, respectively), suggesting that rs6475526 is an independent prognostic marker for CRC. Our data suggest that genetic variation in the IFN signaling pathway genes may play a role in the etiology and survival of CRC and further studies are warranted.

• MeSH
• genetická predispozice k nemoci * MeSH
• genotyp MeSH
• interferony genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * MeSH
• kolorektální nádory genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• multivariační analýza MeSH
• nemocnice MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• rizikové faktory MeSH
• senioři MeSH
• signální transdukce MeSH
• studie případů a kontrol MeSH
• vazebná nerovnováha MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferony MeSH

Type I interferon (IFN) is central to cancer surveillance as it mediates both direct and immune-mediated oncosuppressive effects. A recent study by Perelli et al. suggests that the ability of renal cancer cells to tolerate complex karyotypic alterations elicited by chromosomal instability (CIN), and ultimately acquire full metastatic potential, is also negatively regulated by IFN signaling.

• Klíčová slova
• CGAS, CNV, cancer stem cells, cancer/immunity coevolution, immunoevasion,
• MeSH
• interferon typ I * metabolismus   MeSH
• karcinom z renálních buněk * genetika   MeSH
• lidé MeSH
• nádory ledvin * genetika   MeSH
• nukleotidyltransferasy metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• interferon typ I * MeSH
• nukleotidyltransferasy MeSH

We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41hi) and showed bias for differentiation toward megakaryocytes (Mks). Mouse models of myeloproliferative neoplasms (MPNs) expressing JAK2-V617F (VF) displayed increased frequencies and percentages of the CD41hi vs CD41lo HSCs compared with wild-type controls. An increase in CD41hi HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from patients with MPN. CD41hi HSCs produced a higher number of Mk-colonies of HSCs in single-cell cultures in vitro, but showed reduced long-term reconstitution potential compared with CD41lo HSCs in competitive transplantations in vivo. RNA expression profiling showed an upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41hi HSCs, whereas CD41lo HSCs showed higher gene expression of interferon and the JAK/STAT and TNFα/NFκB signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41hi HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in patients with MPN. Treatment with interferon-α further increased the frequency and percentage of CD41hi HSCs and reduced the number of JAK2-V617F+ HSCs in mice and patients with MPN. The shift toward the CD41hi subset of HSCs by interferon-α provides a possible mechanism of how interferon-α preferentially targets the JAK2 mutant clone.

• MeSH
• bodová mutace účinky léků   MeSH
• genový knockin MeSH
• hematopoetické kmenové buňky cytologie   metabolismus   MeSH
• interferon alfa terapeutické užití   MeSH
• Janus kinasa 2 genetika   MeSH
• lidé MeSH
• megakaryocyty cytologie   metabolismus   MeSH
• myeloproliferativní poruchy farmakoterapie   genetika   MeSH
• myši transgenní MeSH
• myši MeSH
• trombocytový membránový glykoprotein IIb genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferon alfa MeSH
• JAK2 protein, human MeSH Prohlížeč
• Jak2 protein, mouse MeSH Prohlížeč
• Janus kinasa 2 MeSH
• trombocytový membránový glykoprotein IIb MeSH

Treatments of non-small cell lung cancer (NSCLC), the most common form of lung cancer, still remain poor. Interferon alpha (IFN-alpha), an important physiological immunomodulator, possesses direct cytotoxic and cytostatic effects on tumour cells, antiangiogenic effects, and activates anti-tumour immunity. Recently, the IFN-alpha oncologic indications have included melanoma, renal carcinoma, and different types of leukaemia. However, the application of IFN-alpha in therapy of lung cancer has not been validated yet. Herein the human lung carcinoma cell line A549, a model of NSCLC in vitro, was used to pursue the effect of IFN-alpha on A549 cell proliferation and differentiation together with the effect on protein expression and activity of three ATP-transporters mediating multi-drug resistance (MDR). IFN-alpha significantly inhibited the proliferation of A549 cells which was not connected with arrest in a particular cell cycle phase. Further, IFN-alpha-mediated differentiation of A549 was observed based on an increase in alkaline phosphatase activity. Simultaneously, IFN-alpha increased the expression and activity of ATP-transporters mediating MDR. Thus, the IFN-alpha down-regulation of NSCLC cell proliferation was accompanied by a potential of cells to exclude potential therapeutic substances such as chemotherapeutic agents. These effects could have a significant impact on considerations of IFN-alpha as a therapeutic agent for NSCLC.

• MeSH
• ABC transportéry metabolismus   MeSH
• alkalická fosfatasa metabolismus   MeSH
• buněčná diferenciace fyziologie   MeSH
• buněčný cyklus fyziologie   MeSH
• fosforylace MeSH
• interferon alfa metabolismus   MeSH
• karcinom enzymologie   patofyziologie   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory plic enzymologie   patofyziologie   MeSH
• proliferace buněk * MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 metabolismus   MeSH
• viabilita buněk fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• alkalická fosfatasa MeSH
• interferon alfa MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 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.

• Klíčová slova
• ATP, DNA, DNA damage, IRDS genes, RNA, chemotherapy and radiotherapy, functional site, interferon, protein interfaces, receptors, resistance, upstream regulator, viruses,
• MeSH
• adaptorové proteiny signální transdukční fyziologie   MeSH
• aktivace transkripce MeSH
• chemorezistence genetika   fyziologie   MeSH
• dvouvláknová RNA MeSH
• interferonový regulační faktor 7 MeSH
• interferony metabolismus   fyziologie   MeSH
• intracelulární signální peptidy a proteiny MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• poškození DNA genetika   fyziologie   MeSH
• proteiny vázající RNA MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• dvouvláknová RNA MeSH
• IFIT1 protein, human MeSH Prohlížeč
• IFIT3 protein, human MeSH Prohlížeč
• interferonový regulační faktor 7 MeSH
• interferony MeSH
• intracelulární signální peptidy a proteiny MeSH
• IRF7 protein, human MeSH Prohlížeč
• proteiny vázající RNA MeSH
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Similar to other herpesviruses, KSHV has two life cycles, latency and lytic replication. In latency, the KSHV genome persists as a circular episome in the nucleus of the host cell and only a few viral genes are expressed. In this review, we focus on oncogenic, antiapoptotic, and immunomodulating properties of KSHV-encoded homologues of cellular interferon regulatory factors (IRFs)--viral IRF1 (vIRF1) to vIRF4--and their possible role in the KSHV-mediated antiviral response, apoptosis, and oncogenicity.

• MeSH
• apoptóza MeSH
• biologické modely MeSH
• interferonové regulační faktory genetika   imunologie   MeSH
• interferony metabolismus   MeSH
• karcinogeneze MeSH
• lidé MeSH
• lidský herpesvirus 8 genetika   imunologie   patogenita   MeSH
• multigenová rodina MeSH
• signální transdukce MeSH
• virové geny MeSH
• virové proteiny genetika   imunologie   MeSH
• zánět etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• interferonové regulační faktory MeSH
• interferony MeSH
• viral interferon regulatory factors MeSH Prohlížeč
• virové proteiny MeSH