المؤلفون: Dos Santos, Reinaldo S., Guzman-Llorens, Daniel, Perez-Serna, Atenea A., Nadal, Angel, Marroqui, Laura

المصدر: Frontiers in Immunology ; volume 14 ; ISSN 1664-3224

مصطلحات موضوعية: Immunology, Immunology and Allergy

الوصف: Introduction Type 1 diabetes is characterized by pancreatic islet inflammation and autoimmune-driven pancreatic β-cell destruction. Interferon-α (IFNα) is a key player in early human type 1 diabetes pathogenesis. IFNα activates the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway, leading to inflammation, HLA class I overexpression, endoplasmic reticulum (ER) stress, and β-cell apoptosis (in synergy with IL-1β). As TYK2 inhibition has raised as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect β-cells from the effects of IFNα and other proinflammatory cytokines (i.e., IFNγ and IL-1β). Methods All experiments were performed in the human EndoC-βH1 β-cell line. HLA class I expression, inflammation, and ER stress were evaluated by real-time PCR, immunoblotting, and/or immunofluorescence. Apoptosis was assessed by the DNA-binding dyes Hoechst 33342 and propidium iodide or caspase 3/7 activity. The promoter activity was assessed by luciferase assay. Results Deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 activation and MHC class I hyperexpression, in a dose-dependent manner without affecting β-cell survival and function. A comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signaling pathway. Deucravacitinib protected β-cells from the effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially reduce apoptosis and inflammation in cells pre-treated with IFNα + IL-1β or IFNγ + IL-1β. Discussion Our findings suggest that, by protecting β-cells against the deleterious effects of proinflammatory cytokines without affecting β-cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes.

الإتاحة: https://doi.org/10.3389/fimmu.2023.1263926Test

المؤلفون: Babiloni-Chust, Ignacio, Dos Santos, Reinaldo S., Medina-Gali, Regla M., Perez-Serna, Atenea A., Encinar, José A., Martinez-Pinna, Juan, Gustafsson, Jan-Ake, Marroquí, Laura, Nadal, Ángel

المساهمون: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Fisiología Neuroendocrina (FINE)

مصطلحات موضوعية: Apoptosis, Bisphenol-A, Endocrine disruptors, GPER/GPR30, Heterodimers, 17β-estradiol, Estrogen receptors, Fisiología

الوصف: 17β-estradiol protects pancreatic β-cells from apoptosis via the estrogen receptors ERα, ERβ and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ERα and ERβ, or in dispersed islet cells from ERβ knockout (BERKO) mice. However, the ERα and ERβ agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ERα and ERβ form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERβ as well as GPER activation by G1 decreased ERαβ heterodimers. We propose that ERαβ heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ERαβ heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors. ; This work was supported by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) grants BPU2017-86579-R (AN), PID2020-117294RB-I00 (AN, JM-P), Generalitat Valenciana PROMETEO II/2020/006 (AN) and European Union’s Horizon 2020 research and innovation programme under grant agreement GOLIATH No. 825489 (AN). Author laboratories hold grants from Ministerio de Ciencia e Innovación, Agencia Estatal de ...

العلاقة: https://doi.org/10.1016/j.envint.2022.107250Test; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2017-86579-R; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-117294RB-I00; info:eu-repo/grantAgreement/EC/H2020/825489; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096724-B-C21; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-117569RA-I00; Environment International. 2022, 164: 107250. https://doi.org/10.1016/j.envint.2022.107250Test; 0160-4120 (Print); 1873-6750 (Online); http://hdl.handle.net/10045/123120Test

الإتاحة: https://doi.org/10.1016/j.envint.2022.107250Test
http://hdl.handle.net/10045/123120Test

المؤلفون: Marroquí, Laura, Martinez-Pinna, Juan, Castellano-Muñoz, Manuel, Dos Santos, Reinaldo S., Medina-Gali, Regla M., Soriano, Sergi, Quesada, Iván, Gustafsson, Jan-Ake, Encinar, José A., Nadal, Ángel

المساهمون: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Fisiología Neuroendocrina (FINE)

مصطلحات موضوعية: Bisphenol, Islet of langerhans, Endocrine disrupting chemicals, Estrogen receptors, Molecular dynamics simulation, Fisiología

الوصف: Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic β-cells from wild type (WT) and estrogen receptor β (ERβ) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in β-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in β-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERβ pathways. Molecular dynamics simulations indicated differences in ERβ ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERβ whose activation alters three key cellular events in β-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols. ; This work was supported by BPU2017-86579-R (AN) and BFU2016-77125-R (IQ) and RTI2018-096724-B-C21 (JAE) supported by FEDER /Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación, Spain. PROMETEO/2020/006 (AN), PROMETEO/2016/006 (JAE) and SEJI/2018/023 (LM) supported by Generalitat Valenciana, Spain. J-AG was supported by the Robert A. Welch Foundation (E 0004), USA. CIBERDEM is an initiative of the Instituto de Salud Carlos III, Spain.

العلاقة: https://doi.org/10.1016/j.chemosphere.2020.129051Test; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2017-86579-R; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-77125-R; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096724-B-C21; Chemosphere. 2021, 265: 129051. https://doi.org/10.1016/j.chemosphere.2020.129051Test; 0045-6535 (Print); 1879-1298 (Online); http://hdl.handle.net/10045/112363Test

الإتاحة: https://doi.org/10.1016/j.chemosphere.2020.129051Test
http://hdl.handle.net/10045/112363Test

المؤلفون: Colli, Maikel L., Hill, Jessica L. E., Marroquí, Laura, Chaffey, Jessica, Dos Santos, Reinaldo S., Leete, Pia, Coomans de Brachène, Alexandra, Paula, Flavia M. M., Op de Beeck, Anne, Castela, Angela, Marselli, Lorella, Krogvold, Lars, Dahl-Jorgensen, Knut, Marchetti, Piero, Morgan, Noel G., Richardson, Sarah J., Eizirik, Décio L.

المساهمون: Colli, Maikel L., Hill, Jessica L. E., Marroquí, Laura, Chaffey, Jessica, Dos Santos, Reinaldo S., Leete, Pia, Coomans de Brachène, Alexandra, Paula, Flavia M. M., Op de Beeck, Anne, Castela, Angela, Marselli, Lorella, Krogvold, Lar, Dahl-Jorgensen, Knut, Marchetti, Piero, Morgan, Noel G., Richardson, Sarah J., Eizirik, Décio L.

مصطلحات موضوعية: CD274, Immune checkpoint inhibitor, IRF1, Pancreatic beta cell, Pancreatic islet, PDL-1, PDL1, Type 1 diabete, Adolescent, Adult, B7-H1 Antigen, Biomarker, Cell Line, Child, Preschool, Diabetes Mellitus, Type 1, Human, Insulin-Secreting Cell, Interferon Regulatory Factor-1, Interferon-alpha, Interferon-gamma, Islets of Langerhan, Middle Aged, Young Adult, Gene Expression Regulation, Biochemistry, Genetics and Molecular Biology (all)

الوصف: Background: Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated. Methods: The expression of PDL1, IRF1, insulin and glucagon was evaluated in samples of T1D donors by immunofluorescence. Cytokine-induced PDL1 expression in the human beta cell line, EndoC-βH1, and in primary human pancreatic islets was determined by real-time RT-PCR, flow cytometry and Western blot. Specific and previously validated small interference RNAs were used to inhibit STAT1, STAT2, IRF1 and JAK1 signaling. Key results were validated using the JAK inhibitor Ruxolitinib. Findings: PDL1 was present in insulin-positive cells from twelve T1D individuals (6 living and 6 deceased donors) but absent from insulin-deficient islets or from the islets of six non-diabetic controls. Interferons-α and -γ, but not interleukin-1β, induced PDL1 expression in vitro in human islet cells and EndoC-βH1 cells. Silencing of STAT1 or STAT2 individually did not prevent interferon-α-induced PDL1, while blocking of JAKs – a proposed therapeutic strategy for T1D – or IRF1 prevented PDL1 induction. Interpretation: These findings indicate that PDL1 is expressed in beta cells from people with T1D, possibly to attenuate the autoimmune assault, and that it is induced by both type I and II interferons via IRF1.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/30269996; info:eu-repo/semantics/altIdentifier/wos/WOS:000447685300041; volume:36; firstpage:367; lastpage:375; numberofpages:9; journal:EBIOMEDICINE; info:eu-repo/grantAgreement/EC/H2020/115797 667191; http://hdl.handle.net/11568/954955Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85054193057; https://www.sciencedirect.com/science/article/pii/S2352396418303980Test

الإتاحة: https://doi.org/10.1016/j.ebiom.2018.09.040Test
http://hdl.handle.net/11568/954955Test
https://www.sciencedirect.com/science/article/pii/S2352396418303980Test

المؤلفون: Martínez-Pinna, Juan, Marroquí, Laura, Hmadcha, Abdelkrim, López Beas, Javier, Soriano, Sergi, Villar-Pazos, Sabrina, Alonso-Magdalena, Paloma, Santos, Reinaldo, Quesada, Iván, Martin, Franz, Soria Escoms, Bernat

المساهمون: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)

مصطلحات موضوعية: Insulin, Insulin-Secreting Cells, Glucose-stimulated insulin, Diabetes, Beta cell

الوصف: Aims/hypothesis: Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical that has been associated with type 2 diabetes development. Low doses of BPA modify pancreatic beta cell function and induce insulin resistance; some of these effects are mediated via activation of oestrogen receptors α (ERα) and β (ERβ). Here we investigated whether low doses of BPA regulate the expression and function of ion channel subunits involved in beta cell function. Methods: Microarray gene profiling of isolated islets from vehicle- and BPA-treated (100 μg/kg per day for 4 days) mice was performed using Affymetrix GeneChip Mouse Genome 430.2 Array. Expression level analysis was performed using the normalisation method based on the processing algorithm ‘robust multi-array average’. Whole islets or dispersed islets from C57BL/6J or oestrogen receptor β (ERβ) knockout (Erβ−/−) mice were treated with vehicle or BPA (1 nmol/l) for 48 h. Whole-cell patch-clamp recordings were used to measure Na+ and K+ currents. mRNA expression was evaluated by quantitative real-time PCR. Results: Microarray analysis showed that BPA modulated the expression of 1440 probe sets (1192 upregulated and 248 downregulated genes). Of these, more than 50 genes, including Scn9a, Kcnb2, Kcnma1 and Kcnip1, encoded important Na+ and K+ channel subunits. These findings were confirmed by quantitative RT-PCR in islets from C57BL/6J BPA-treated mice or whole islets treated ex vivo. Electrophysiological measurements showed a decrease in both Na+ and K+ currents in BPA-treated islets. The pharmacological profile indicated that BPA reduced currents mediated by voltage-activated K+ channels (Kv2.1/2.2 channels) and large-conductance Ca2+-activated K+ channels (KCa1.1 channels), which agrees with BPA’s effects on gene expression. Beta cells from ERβ−/− mice did not present BPA-induced changes, suggesting that ERβ mediates BPA’s effects in pancreatic islets. Finally, BPA increased burst duration, reduced the amplitude of the action potential and enlarged the action ...

العلاقة: Diabetología, 62 (9), 1667-1680.; BPU2017-86579-R; SAF2014-58335-P; BFU2016-77125-R; SAF2017-90604-REDT; PI16/00259; PI17/02104; RD16/0011/0034; IJCI-2015-24482; http://doi.org/10.1007/s00125-019-4925-yTest; https://idus.us.es/handle//11441/89179Test

الإتاحة: https://doi.org/10.1007/s00125-019-4925-yTest
https://idus.us.es/handle//11441/89179Test

المؤلفون: Soriano, Sergi, Gil-Rivera, Minerva, Marroquí, Laura, Alonso Magdalena, Paloma, Fuentes, Esther, Gustafsson, Jan-Ake, Nadal, Ángel, Martinez-Pinna, Juan

المساهمون: Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Fisiología Neuroendocrina (FINE)

مصطلحات موضوعية: Bisphenol A, Nociception, Sodium channels, Dorsal root ganglion, Fisiología

الوصف: 17β-Estradiol mediates the sensitivity to pain and is involved in sex differences in nociception. The widespread environmental disrupting chemical bisphenol A (BPA) has estrogenic activity, but its implications in pain are mostly unknown. Here we show that treatment of male mice with BPA (50 µg/kg/day) during 8 days, decreases the latency to pain behavior in response to heat, suggesting increased pain sensitivity. We demonstrate that incubation of dissociated dorsal root ganglia (DRG) nociceptors with 1 nM BPA increases the frequency of action potential firing. SCN9A encodes the voltage-gated sodium channel Nav1.7, which is present in DRG nociceptors and is essential in pain signaling. Nav1.7 and other voltage-gated sodium channels in mouse DRG are considered threshold channels because they produce ramp currents, amplifying small depolarizations and enhancing electrical activity. BPA increased Nav-mediated ramp currents elicited with slow depolarizations. Experiments using pharmacological tools as well as DRG from ERβ−/− mice indicate that this BPA effect involves ERα and phosphoinositide 3-kinase. The mRNA expression and biophysical properties other than ramp currents of Nav channels, were unchanged by BPA. Our data suggest that BPA at environmentally relevant doses affects the ability to detect noxious stimuli and therefore should be considered when studying the etiology of pain conditions. ; The authors’ laboratories are funded by the Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER), BFU2017-86579-R (A.N.) and Generalitat Valenciana, PROMETEOII/2015/016 (A.N.). CIBERDEM is an initiative of the Instituto de Salud Carlos III. J.-A. G. was supported by a fellowship from the A. Welch Foundation (Grant E-0004).

العلاقة: https://doi.org/10.1038/s41598-019-46769-6Test; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2017-86579-R; Scientific Reports. 2019, 9: 10306. doi:10.1038/s41598-019-46769-6; http://hdl.handle.net/10045/94727Test

الإتاحة: https://doi.org/10.1038/s41598-019-46769-6Test
http://hdl.handle.net/10045/94727Test

المؤلفون: Bru-Tari, Eva, Cobo-Vuilleumier, Nadia, Alonso-Magdalena, Paloma, Dos Santos, Reinaldo S, Marroqui, Laura, Nadal, Angel, Gauthier, Benoit R, Quesada, Ivan

مصطلحات موضوعية: Animals, B7-1 Antigen, Cell Proliferation, Cell Transdifferentiation, Diabetes Mellitus, Experimental, Disease Models, Animal, Glucagon, Glucagon-Secreting Cells, Homeodomain Proteins, Hyperglycemia, Insulin, Mice, Inbred C57BL, Transgenic, Trans-Activators

الوصف: Most studies in type 1 diabetes (T1D) have focused on the loss of the pancreatic beta-cell population. However, despite the involvement of the alpha-cell in the aetiology and complications of T1D, little is known about the regulation of the pancreatic alpha-cell mass in this disease. The need for a better understanding of this process is further emphasized by recent findings suggesting that alpha-cells may constitute a potential reservoir for beta-cell regeneration. In this study, we characterized the pancreatic alpha-cell mass and its regulatory processes in the transgenic RIP-B7.1 mice model of experimental autoimmune diabetes (EAD). Diabetic mice presented insulitis, hyperglycaemia, hypoinsulinemia and hyperglucagonemia along with lower pancreatic insulin content. While alpha-cell mass and pancreatic glucagon content were preserved at the early-onset of EAD, both parameters were reduced in the advanced phase. At both stages, alpha-cell size, proliferation and ductal neogenesis were up-regulated, whereas apoptosis was almost negligible. Interestingly, we found an increase in the proportion of glucagon-containing cells positive for insulin or the beta-cell transcription factor PDX1. Our findings suggest that pancreatic alpha-cell renewal mechanisms are boosted during the natural course of EAD, possibly as an attempt to maintain the alpha-cell population and/or to increase beta-cell regeneration via alpha-cell transdifferentiation.

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/10668/14211Test; PMC6606577; https://www.nature.com/articles/s41598-019-45853-1.pdfTest; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606577/pdfTest

الإتاحة: https://doi.org/10.1038/s41598-019-45853-1Test
http://hdl.handle.net/10668/14211Test
https://www.nature.com/articles/s41598-019-45853-1.pdfTest
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606577/pdfTest

المؤلفون: GRIECO, FABIO ARTURO, SEBASTIANI, GUIDO, Juan Mateu, Jonas, Villate, Olatz, Marroqui, Laura, Ladrière, Laurence, Tugay, Ksenya, Regazzi, Romano, Bugliani, Marco, Marchetti, Piero, DOTTA, FRANCESCO, Eizirik, Décio L.

المساهمون: Grieco, FABIO ARTURO, Sebastiani, Guido, Juan Mateu, Jona, Villate, Olatz, Marroqui, Laura, Ladrière, Laurence, Tugay, Ksenya, Regazzi, Romano, Bugliani, Marco, Marchetti, Piero, Dotta, Francesco, Eizirik, Décio L.

مصطلحات موضوعية: Internal Medicine, Endocrinology, Diabetes and Metabolism

الوصف: Type 1 diabetes (T1D) is an autoimmune disease leading to β-cell destruction. MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression and organ formation. They participate in the pathogenesis of several autoimmune diseases, but the nature of miRNAs contributing to β-cell death in T1D and their target genes remain to be clarified.We performed an miRNA expression profile on human islet preparations exposed to the cytokines IL-1β plus IFN-γ. Confirmation of miRNA and target gene modification in human β-cells was performed by real-time quantitative PCR. Single-stranded miRNAs inhibitors were used to block selected endogenous miRNAs. Cell death was measured by Hoechst/propidium iodide staining and activation of caspase-3. Fifty-seven miRNAs were detected as modulated by cytokines. Three of them, namely miR-23a-3p, miR-23b-3p, and miR-149-5p, were downregulated by cytokines and selected for further studies. These miRNAs were found to regulate the expression of the proapoptotic Bcl-2 proteins DP5 and PUMA and consequent human β-cell apoptosis. These results identify a novel cross talk between a key family of miRNAs and proapoptotic Bcl-2 proteins in human pancreatic β-cells, broadening our understanding of cytokine-induced β-cell apoptosis in early T1D.

وصف الملف: STAMPA

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/27737950; info:eu-repo/semantics/altIdentifier/wos/WOS:000390834300015; volume:66; issue:1; firstpage:100; lastpage:112; numberofpages:13; journal:DIABETES; http://hdl.handle.net/11365/1003882Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85007307434; https://diabetesjournals.org/diabetes/article/66/1/100/40160/MicroRNAs-miR-23a-3p-miR-23b-3p-and-miR-149-5pTest; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204315Test/

الإتاحة: https://doi.org/10.2337/db16-0592Test
http://hdl.handle.net/11365/1003882Test
https://diabetesjournals.org/diabetes/article/66/1/100/40160/MicroRNAs-miR-23a-3p-miR-23b-3p-and-miR-149-5pTest
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204315Test/

المؤلفون: Dos Santos, Reinaldo S., Marroquí, Laura, Velayos Gainza, Teresa, Olazagoitia Garmendia, Ane, Jauregi Miguel, Amaia, Castellanos Rubio, Ainara, Eizirik, Decio L., Castaño González, Luis Antonio, Santín Gómez, Izortze

المساهمون: European Commission

مصطلحات موضوعية: susceptibility gene, type 1 diabetes, pancreatic beta cell, inflammation, viral infection, type I IFNs, DEXI

الوصف: Aims/hypothesis: The initial stages of type 1 diabetes are characterized by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A has been considered the etiologic gene in the region. However, recent gene expression analysis indicates that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI. We presently evaluated the role of DEXI in beta cell responses to “danger signals” and determined the mechanisms involved. Methods: Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Viral double-stranded RNA-driven beta cell inflammation and apoptosis were evaluated by RT-PCR, western blot and luciferase assays. Results: DEXI-silenced beta cells exposed to double-stranded RNA (PIC; a by-product of viral replication) showed reduced STAT1 activation and lower production of pro-inflammatory chemokines that was preceded by a reduction in IFN expression. Exposure to PIC increased chromatin-bound DEXI and IFN promoter activity. This effect on IFN promoter was inhibited in DEXI-silenced betacells, suggesting that DEXI is implicated in the regulation of IFNtranscription. In a mirror image of knockdown experiments, DEXI overexpression led to increased STAT1 and pro-inflammatory chemokine expression. Conclusions: These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune response in beta cells. Moreover, our results provide initial information on the function of DEXI. ; This work was supported by a Research Project Grant from the Basque Department of Health (2015111068), a Research Grant from Fundación de la Sociedad Española de Diabetes (FSED), the Horizon 2020 Program T2Dsystems (GA667191) and ...

وصف الملف: application/pdf

العلاقة: info:eu-repo/grantAgreement/EC/H2020/GA667191; https://doi.org/10.1007/s00125-018-4782-0Test; Diabetologia 62(3) : 459-472 (2019); http://hdl.handle.net/10810/64679Test

الإتاحة: https://doi.org/10.1007/s00125-018-4782-0Test
http://hdl.handle.net/10810/64679Test

المؤلفون: Dos Santos, Reinaldo Sousa, Marroqui, Laura, Velayos, Teresa, Olazagoitia-Garmendia, Ane, Jauregi-Miguel, Amaia, Castellanos-Rubio, Ainara, Eizirik, Decio L., Castaňo, Luis, Santin, Izortze

المصدر: Diabetologia

مصطلحات موضوعية: Sciences bio-médicales et agricoles, DEXI, Inflammation, Pancreatic beta cell, Susceptibility gene, Type 1 diabetes, Type I IFNs, Viral infection

الوصف: The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI, encoding dexamethasone-induced protein (DEXI). We therefore evaluated the role of DEXI in beta cell responses to 'danger signals' and determined the mechanisms involved. ; SCOPUS: ar.j ; info:eu-repo/semantics/published

وصف الملف: 1 full-text file(s): application/pdf

العلاقة: uri/info:doi/10.1007/s00125-018-4782-0; uri/info:pii/10.1007/s00125-018-4782-0; uri/info:pmid/30478640; uri/info:scp/85057526954; https://dipot.ulb.ac.be/dspace/bitstream/2013/283287/4/DosSantos2018_Article_DEXIACandidateGeneForType1Diab.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/283287Test

الإتاحة: http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/283287Test
https://dipot.ulb.ac.be/dspace/bitstream/2013/283287/4/DosSantos2018_Article_DEXIACandidateGeneForType1Diab.pdfTest