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- Title
JAK‐1 Inhibition Suppresses Interferon‐Induced BAFF Production in Human Salivary Gland.
- Authors
Lee, Jaeseon; Lee, Jennifer; Kwok, Seung‐Ki; Baek, SeungYe; Jang, Se Gwang; Hong, Seung‐Min; Min, Jae‐Woong; Choi, Sun Shim; Lee, Juhyun; Cho, Mi‐La; Park, Sung‐Hwan
- Abstract
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 Sjögren'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.
- Subjects
ANIMAL experimentation; CELLULAR signal transduction; EPITHELIAL cells; GENE expression; INTRAPERITONEAL injections; INTERFERONS; LYMPHOCYTES; MICE; NEUROTRANSMITTER uptake inhibitors; POLYMERASE chain reaction; SALIVARY glands; SJOGREN'S syndrome; TUMOR necrosis factors; REVERSE transcriptase polymerase chain reaction; JANUS kinases; PHARMACODYNAMICS
- Publication
Arthritis & Rheumatology, 2018, Vol 70, Issue 12, p2057
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.40589