구.추천논문
Jaeseon Lee,1 Jennifer Lee,2 Seung-Ki Kwok,2 SeungYe Baek,1 Se Gwang Jang,1 Seung-Min Hong,1 Jae-Woong Min,3 Sun Shim Choi,3 Juhyun Lee,1 Mi-La Cho,1 and Sung-Hwan Park2,*
1The Catholic University of Korea, Seoul, Republic of Korea; 2 The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Republic of Korea; 3 Kangwon National University, Chuncheon, Republic of Korea.
*Address correspondence to Sung-Hwan Park, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Collegeof Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Banpo-daero 222, Seocho-gu, Seoul 06591, Republic of Korea.
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.
논문정보
관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기