Janus kinase 1 inhibition suppresses interferon-induced B cell activating factor production in human salivary gland: potential therapeutic strategy for primary Sjögren's syndrome.

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 IFN alpha- and IFN gamma-induced pSTAT-1(Y701), pSTAT-3(Y705), and protein inhibitor of activated STAT-3 (PIAS-3) in human SGECs as well as IFN gamma-induced pSTAT-1(Y701), pSTAT-3(S727), and PIAS-1 in mouse SGECs. Conclusion JAK inhibition controls aberrant activation of SGECs and may be a novel therapeutic approach for primary SS.