{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:39:30Z","timestamp":1789533570216,"version":"build-2803163510"},"reference-count":18,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2017,6,5]],"date-time":"2017-06-05T00:00:00Z","timestamp":1496620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001677","name":"Institut national de la sant\u00e9 et de la recherche m\u00e9dicale","doi-asserted-by":"publisher","award":["000427993"],"award-info":[{"award-number":["000427993"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["GA 309449"],"award-info":[{"award-number":["GA 309449"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201010\u2010IAHU\u201001"],"award-info":[{"award-number":["ANR\u201010\u2010IAHU\u201001"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Gain\u2010of\u2010function mutations in <jats:italic>TMEM173<\/jats:italic>, encoding the stimulator of interferon (IFN) genes (STING) protein, underlie a novel type I interferonopathy that is minimally responsive to conventional immunosuppressive therapies and associated with high frequency of childhood morbidity and mortality. STING gain\u2010of\u2010function causes constitutive oversecretion of IFN. This study was undertaken to determine the effects of a TANK\u2010binding kinase 1 (TBK\u20101)\/IKK\u025b inhibitor (BX795) on secretion and signaling of IFN in primary peripheral blood mononuclear cells (PBMCs) from patients with mutations in STING.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PBMCs from 4 patients with STING\u2010associated disease were treated with BX795. The effect of BX795 on IFN pathways was assessed by Western blotting and an IFN\u03b2 reporter assay, as well as by quantification of IFN\u03b1 in cell lysates, staining for STAT\u20101 phosphorylation, and measurement of IFN\u2010stimulated gene (ISG) messenger RNA (mRNA) expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment of PBMCs with BX795 inhibited the phosphorylation of IFN regulatory factor 3 and IFN\u03b2 promoter activity induced in HEK 293T cells by cyclic GMP\u2010AMP or by genetic activation of STING. In vitro exposure to BX795 inhibited IFN\u03b1 production in PBMCs of patients with STING\u2010associated disease without affecting cell survival. In addition, BX795 decreased STAT\u20101 phosphorylation and ISG mRNA expression independent of IFN\u03b1 blockade.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings demonstrate the effect of BX795 on reducing type I IFN production and IFN signaling in cells from patients with gain\u2010of\u2010function mutations in STING. A combined inhibition of TBK\u20101 and IKK\u025b therefore holds potential for the treatment of patients carrying STING mutations, and may also be relevant in other type I interferonopathies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40122","type":"journal-article","created":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T15:50:44Z","timestamp":1492703444000},"page":"1495-1501","source":"Crossref","is-referenced-by-count":27,"title":["Brief Report: Blockade of TANK\u2010Binding Kinase 1\/IKK\u025b Inhibits Mutant Stimulator of Interferon Genes (STING)\u2013Mediated Inflammatory Responses in Human Peripheral Blood Mononuclear Cells"],"prefix":"10.1002","volume":"69","author":[{"given":"Marie\u2010Louise","family":"Fr\u00e9mond","sequence":"first","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine, INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, and Pediatric Hematology\u2010Immunology and Rheumatology Department, H\u00f4pital Necker\u2010Enfants Malades, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Uggenti","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine and INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lien","family":"Van Eyck","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine and INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Melki","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine, INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Pediatric Hematology\u2010Immunology and Rheumatology Department, H\u00f4pital Necker\u2010Enfants Malades, AP\u2010HP, and General Pediatrics, Infectious Diseases and Internal Medicine Department, H\u00f4pital Robert Debr\u00e9, AP\u2010HP Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Bondet","sequence":"additional","affiliation":[{"name":"INSERM UMR 1223 and Laboratory of Dendritic Cell Immunobiology, Institut Pasteur Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Kitabayashi","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine and INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Hertel","sequence":"additional","affiliation":[{"name":"ImmunoQure Du\u00a8sseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Hayday","sequence":"additional","affiliation":[{"name":"ImmunoQure Du\u00a8sseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Neven","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine, Pediatric Hematology\u2010Immunology and Rheumatology Department, H\u00f4pital Necker\u2010Enfants Malades, AP\u2010HP, and INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoann","family":"Rose","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine and INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darragh","family":"Duffy","sequence":"additional","affiliation":[{"name":"Darragh Duffy, PhD: INSERM UMR 1223, and Laboratory of Dendritic Cell Immunobiology Institut Pasteur, and Center for Translational Research, Institut Pasteur Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanick J.","family":"Crow","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine, INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France, and University of Manchester Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu P.","family":"Rodero","sequence":"additional","affiliation":[{"name":"Paris Descartes University, Sorbonne\u2010Paris\u2010Cit\u00e9, Institut Imagine and INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation Paris 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