DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway
Aims/hypothesis 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...
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| Veröffentlicht in: | Diabetologia 2019-03, Vol.62 (3), p.459-472 |
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| creator | Dos Santos, Reinaldo S. Marroqui, Laura Velayos, Teresa Olazagoitia-Garmendia, Ane Jauregi-Miguel, Amaia Castellanos-Rubio, Ainara Eizirik, Decio L. Castaño, Luis Santin, Izortze |
| description | Aims/hypothesis
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.
Methods
Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays.
Results
DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and
IFNβ
promoter activity. This effect on
IFNβ
promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of
IFNβ
transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines.
Conclusions/interpretation
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 responses in beta cells. Moreover, our results provide initial information on the function of DEXI. |
| doi_str_mv | 10.1007/s00125-018-4782-0 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2137639438</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2137639438</sourcerecordid><originalsourceid>FETCH-LOGICAL-c415t-d634481c9e43ae5ece266b7b24272ca82df348be8d77f2528ef8347fda58ba523</originalsourceid><addsrcrecordid>eNp1kc1u1TAQhS0EoreFB2CDRmLbUP8lcZdV_7hSBQsuUneWE49zUyXOxXZA92V4VhylwIrVeGa-c8bSIeQdox8ZpfVFpJTxsqBMFbJWvKAvyIZJkR-Sq5dks6wLpqrHE3Ia4xOlVJSyek1OBM18JemG_Lq5fdyeg4HWeNtbkxA69AhuCpCOBwQGtjcNJoznME52HjISIZgEWQD7eTQeDsa3AU3qW8hk9sJhgN67wYxjnk4efvQGAnaLemknB2mP64EtbO8-X3zdXe0g9p03w9D7Llum_U9zfENeOTNEfPtcz8i3u9vd9afi4cv99vrqoWglK1NhKyGlYu0lSmGwxBZ5VTV1wyWveWsUt05I1aCyde14yRU6JWTtrClVY0ouzsiH1fcQpu8zxqSfpjnkz0TNmagrcSmFyhRbqTZMMQZ0-hD60YSjZlQvieg1EZ0T0UsimmbN-2fnuRnR_lX8iSADfAViXvkOw7_T_3f9DUhAlsc</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2137639438</pqid></control><display><type>article</type><title>DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Dos Santos, Reinaldo S. ; Marroqui, Laura ; Velayos, Teresa ; Olazagoitia-Garmendia, Ane ; Jauregi-Miguel, Amaia ; Castellanos-Rubio, Ainara ; Eizirik, Decio L. ; Castaño, Luis ; Santin, Izortze</creator><creatorcontrib>Dos Santos, Reinaldo S. ; Marroqui, Laura ; Velayos, Teresa ; Olazagoitia-Garmendia, Ane ; Jauregi-Miguel, Amaia ; Castellanos-Rubio, Ainara ; Eizirik, Decio L. ; Castaño, Luis ; Santin, Izortze</creatorcontrib><description>Aims/hypothesis
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.
Methods
Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays.
Results
DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and
IFNβ
promoter activity. This effect on
IFNβ
promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of
IFNβ
transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines.
Conclusions/interpretation
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 responses in beta cells. Moreover, our results provide initial information on the function of DEXI.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-018-4782-0</identifier><identifier>PMID: 30478640</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Antiviral drugs ; Apoptosis ; Apoptosis - genetics ; Beta cells ; Chemokines ; Chromatin ; Chromosome 16 ; Dexamethasone ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (insulin dependent) ; Diabetes Mellitus, Type 1 - genetics ; Diabetes Mellitus, Type 1 - metabolism ; Diabetes Mellitus, Type 1 - pathology ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Double-stranded RNA ; Environmental factors ; Gene expression ; Gene regulation ; Human Physiology ; Humans ; Immune response ; Inflammation ; Inflammation - genetics ; Inflammation - metabolism ; Inflammation - pathology ; Insulin-Secreting Cells - metabolism ; Insulin-Secreting Cells - pathology ; Interferon ; Interferon Type I - metabolism ; Internal Medicine ; Medicine ; Medicine & Public Health ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Metabolic Diseases ; Pancreas ; Polymorphism, Single Nucleotide ; Rats ; RNA, Double-Stranded ; Rodents ; Signal transduction ; Signal Transduction - genetics ; Single-nucleotide polymorphism ; STAT Transcription Factors - metabolism ; Stat1 protein ; Transcription ; Western blotting</subject><ispartof>Diabetologia, 2019-03, Vol.62 (3), p.459-472</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2018</rights><rights>Diabetologia is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-d634481c9e43ae5ece266b7b24272ca82df348be8d77f2528ef8347fda58ba523</citedby><cites>FETCH-LOGICAL-c415t-d634481c9e43ae5ece266b7b24272ca82df348be8d77f2528ef8347fda58ba523</cites><orcidid>0000-0003-1651-6776</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00125-018-4782-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00125-018-4782-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30478640$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dos Santos, Reinaldo S.</creatorcontrib><creatorcontrib>Marroqui, Laura</creatorcontrib><creatorcontrib>Velayos, Teresa</creatorcontrib><creatorcontrib>Olazagoitia-Garmendia, Ane</creatorcontrib><creatorcontrib>Jauregi-Miguel, Amaia</creatorcontrib><creatorcontrib>Castellanos-Rubio, Ainara</creatorcontrib><creatorcontrib>Eizirik, Decio L.</creatorcontrib><creatorcontrib>Castaño, Luis</creatorcontrib><creatorcontrib>Santin, Izortze</creatorcontrib><title>DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><addtitle>Diabetologia</addtitle><description>Aims/hypothesis
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.
Methods
Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays.
Results
DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and
IFNβ
promoter activity. This effect on
IFNβ
promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of
IFNβ
transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines.
Conclusions/interpretation
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 responses in beta cells. Moreover, our results provide initial information on the function of DEXI.</description><subject>Animals</subject><subject>Antiviral drugs</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Beta cells</subject><subject>Chemokines</subject><subject>Chromatin</subject><subject>Chromosome 16</subject><subject>Dexamethasone</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diabetes Mellitus, Type 1 - metabolism</subject><subject>Diabetes Mellitus, Type 1 - pathology</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Double-stranded RNA</subject><subject>Environmental factors</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Immune response</subject><subject>Inflammation</subject><subject>Inflammation - genetics</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Insulin-Secreting Cells - pathology</subject><subject>Interferon</subject><subject>Interferon Type I - metabolism</subject><subject>Internal Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Metabolic Diseases</subject><subject>Pancreas</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Rats</subject><subject>RNA, Double-Stranded</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Single-nucleotide polymorphism</subject><subject>STAT Transcription Factors - metabolism</subject><subject>Stat1 protein</subject><subject>Transcription</subject><subject>Western blotting</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc1u1TAQhS0EoreFB2CDRmLbUP8lcZdV_7hSBQsuUneWE49zUyXOxXZA92V4VhylwIrVeGa-c8bSIeQdox8ZpfVFpJTxsqBMFbJWvKAvyIZJkR-Sq5dks6wLpqrHE3Ia4xOlVJSyek1OBM18JemG_Lq5fdyeg4HWeNtbkxA69AhuCpCOBwQGtjcNJoznME52HjISIZgEWQD7eTQeDsa3AU3qW8hk9sJhgN67wYxjnk4efvQGAnaLemknB2mP64EtbO8-X3zdXe0g9p03w9D7Llum_U9zfENeOTNEfPtcz8i3u9vd9afi4cv99vrqoWglK1NhKyGlYu0lSmGwxBZ5VTV1wyWveWsUt05I1aCyde14yRU6JWTtrClVY0ouzsiH1fcQpu8zxqSfpjnkz0TNmagrcSmFyhRbqTZMMQZ0-hD60YSjZlQvieg1EZ0T0UsimmbN-2fnuRnR_lX8iSADfAViXvkOw7_T_3f9DUhAlsc</recordid><startdate>20190301</startdate><enddate>20190301</enddate><creator>Dos Santos, Reinaldo S.</creator><creator>Marroqui, Laura</creator><creator>Velayos, Teresa</creator><creator>Olazagoitia-Garmendia, Ane</creator><creator>Jauregi-Miguel, Amaia</creator><creator>Castellanos-Rubio, Ainara</creator><creator>Eizirik, Decio L.</creator><creator>Castaño, Luis</creator><creator>Santin, Izortze</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><orcidid>https://orcid.org/0000-0003-1651-6776</orcidid></search><sort><creationdate>20190301</creationdate><title>DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway</title><author>Dos Santos, Reinaldo S. ; Marroqui, Laura ; Velayos, Teresa ; Olazagoitia-Garmendia, Ane ; Jauregi-Miguel, Amaia ; Castellanos-Rubio, Ainara ; Eizirik, Decio L. ; Castaño, Luis ; Santin, Izortze</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-d634481c9e43ae5ece266b7b24272ca82df348be8d77f2528ef8347fda58ba523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antiviral drugs</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Beta cells</topic><topic>Chemokines</topic><topic>Chromatin</topic><topic>Chromosome 16</topic><topic>Dexamethasone</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Diabetes Mellitus, Type 1 - metabolism</topic><topic>Diabetes Mellitus, Type 1 - pathology</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Double-stranded RNA</topic><topic>Environmental factors</topic><topic>Gene expression</topic><topic>Gene regulation</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Immune response</topic><topic>Inflammation</topic><topic>Inflammation - genetics</topic><topic>Inflammation - metabolism</topic><topic>Inflammation - pathology</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Insulin-Secreting Cells - pathology</topic><topic>Interferon</topic><topic>Interferon Type I - metabolism</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Metabolic Diseases</topic><topic>Pancreas</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Rats</topic><topic>RNA, Double-Stranded</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signal Transduction - genetics</topic><topic>Single-nucleotide polymorphism</topic><topic>STAT Transcription Factors - metabolism</topic><topic>Stat1 protein</topic><topic>Transcription</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dos Santos, Reinaldo S.</creatorcontrib><creatorcontrib>Marroqui, Laura</creatorcontrib><creatorcontrib>Velayos, Teresa</creatorcontrib><creatorcontrib>Olazagoitia-Garmendia, Ane</creatorcontrib><creatorcontrib>Jauregi-Miguel, Amaia</creatorcontrib><creatorcontrib>Castellanos-Rubio, Ainara</creatorcontrib><creatorcontrib>Eizirik, Decio L.</creatorcontrib><creatorcontrib>Castaño, Luis</creatorcontrib><creatorcontrib>Santin, Izortze</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dos Santos, Reinaldo S.</au><au>Marroqui, Laura</au><au>Velayos, Teresa</au><au>Olazagoitia-Garmendia, Ane</au><au>Jauregi-Miguel, Amaia</au><au>Castellanos-Rubio, Ainara</au><au>Eizirik, Decio L.</au><au>Castaño, Luis</au><au>Santin, Izortze</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway</atitle><jtitle>Diabetologia</jtitle><stitle>Diabetologia</stitle><addtitle>Diabetologia</addtitle><date>2019-03-01</date><risdate>2019</risdate><volume>62</volume><issue>3</issue><spage>459</spage><epage>472</epage><pages>459-472</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>Aims/hypothesis
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.
Methods
Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays.
Results
DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and
IFNβ
promoter activity. This effect on
IFNβ
promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of
IFNβ
transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines.
Conclusions/interpretation
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 responses in beta cells. Moreover, our results provide initial information on the function of DEXI.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>30478640</pmid><doi>10.1007/s00125-018-4782-0</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-1651-6776</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Diabetologia, 2019-03, Vol.62 (3), p.459-472 |
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| source | MEDLINE; SpringerLink Journals |
| subjects | Animals Antiviral drugs Apoptosis Apoptosis - genetics Beta cells Chemokines Chromatin Chromosome 16 Dexamethasone Diabetes Diabetes mellitus Diabetes mellitus (insulin dependent) Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - metabolism Diabetes Mellitus, Type 1 - pathology DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Double-stranded RNA Environmental factors Gene expression Gene regulation Human Physiology Humans Immune response Inflammation Inflammation - genetics Inflammation - metabolism Inflammation - pathology Insulin-Secreting Cells - metabolism Insulin-Secreting Cells - pathology Interferon Interferon Type I - metabolism Internal Medicine Medicine Medicine & Public Health Membrane Proteins - genetics Membrane Proteins - metabolism Metabolic Diseases Pancreas Polymorphism, Single Nucleotide Rats RNA, Double-Stranded Rodents Signal transduction Signal Transduction - genetics Single-nucleotide polymorphism STAT Transcription Factors - metabolism Stat1 protein Transcription Western blotting |
| title | DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway |
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