JAK ‐1 Inhibition Suppresses Interferon‐Induced BAFF Production in Human Salivary Gland
| العنوان: | |
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| المؤلفون: | Seung Ki Kwok, Seung Min Hong, Sung Hwan Park, Jae Woong Min, Mi La Cho, Jennifer Lee, J.H. Lee, Seung Ye Baek, Se Gwang Jang, Jaeseon Lee, Sun Shim Choi |
| المصدر: | Arthritis & Rheumatology. 70:2057-2066 |
| بيانات النشر: | Wiley, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Pyridines, Immunology, Nod, Biology, Peripheral blood mononuclear cell, Salivary Glands, Mice, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, Rheumatology, Mice, Inbred NOD, Interferon, B-Cell Activating Factor, medicine, Animals, Humans, Immunology and Allergy, Secretion, RNA, Messenger, B-cell activating factor, 030203 arthritis & rheumatology, Messenger RNA, Gene knockdown, Janus kinase 1, Epithelial Cells, Janus Kinase 1, Triazoles, Disease Models, Animal, Sjogren's Syndrome, 030104 developmental biology, Leukocytes, Mononuclear, Cancer research, Interferons, Signal Transduction, medicine.drug |
| الوصف: | Objective To examine whether a JAK inhibitor regulates functional responses of human salivary gland epithelial cells (SGECs) and disease parameters in an animal model of Sjogren's syndrome (SS). Methods Common differentially expressed genes (DEGs) were analyzed among peripheral blood mononuclear cells from patients with primary SS and other data sets, using blood and SG tissue. Validation of expression in SGs was analyzed by focus score. Inhibition of messenger RNA expression of DEGs and BAFF by filgotinib was analyzed using reverse transcription-polymerase chain reaction in primary SGECs. SG organoid cultures were used to determine the association between DEGs and BAFF via knockdown using small interfering RNAs or to determine regulation of BAFF by JAK inhibitor. Filgotinib (1.5 mg/kg) was intraperitoneally injected into 8-week-old NOD/ShiLtJ mice 3 times per week to analyze manifestations of disease. Finally, STAT signaling was assessed in human and mouse SGECs. Results Expression of the DEGs IFNG and BAFF increased in SGs from patients with primary SS, as assessed by focus score. There was a significant correlation between IFIT2 and BAFF expression. JAK inhibitor suppressed interferon (IFN)-induced transcription of DEGs and BAFF in human primary SGECs. Knockdown of DEGs or inhibition of JAK caused reduced secretion of BAFF in human SG organoid cultures. In addition, filgotinib-treated mice exhibited increased salivary flow rates and marked reductions in lymphocytic infiltration of SGs. JAK inhibitor regulated IFNα- and IFNγ-induced pSTAT-1Y701 , pSTAT-3Y705 , and protein inhibitor of activated STAT-3 (PIAS-3) in human SGECs as well as IFNγ-induced pSTAT-1Y701 , pSTAT-3S727 , and PIAS-1 in mouse SGECs. Conclusion JAK inhibition controls aberrant activation of SGECs and may be a novel therapeutic approach for primary SS. |
| تدمد: | 2326-5205 2326-5191 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::594391d84dc14b46077289ffdb8bc7ff https://doi.org/10.1002/art.40589 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....594391d84dc14b46077289ffdb8bc7ff |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23265205 23265191 |
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