Importance of serine727 phosphorylated STAT1 in IFN[gamma]-induced signaling and apoptosis of human salivary gland cells

Aim: It is reported that in salivary glands of Sjögren's syndrome (SS), interferon gamma (IFN[gamma]) and IFN[gamma]-inducible genes containing signal transducers and activators of transcription 1 (STAT1) are upregulated and play a crucial role in the pathogenesis of SS. The aim of this study is to clarify which phosphorylation of STAT1, serine727 (Ser727) or tyrosine701 (Tyr701) of STAT1, is important for IFN[gamma] signaling and IFN[gamma]-induced apoptosis in salivary gland cells. Methods: We established STAT1 Tyr701 variant (tyrosine to phenylalanine; Y701F) and STAT1 Ser727 variant (serine to alanine; S727A), which were transfected into human salivary gland (HSG) cells. HSG cells transfected with these mutant-STAT1 were analyzed on the expression of IFN[gamma]-inducible genes and apoptosis after stimulation with IFN[gamma]. Results: In Y701F mutant-STAT1 transfected HSG cells (Ser727-dominant HSG cells), IFN[gamma]-inducible genes such as IP10, IRF1, and Fas expression were increased after stimulation with IFN[gamma]. In Ser727-dominant HSG cells, the induction of apoptosis after stimulation with IFN[gamma] was also increased compared with S727A mutant-STAT1 transfected HSG cells (Tyr701-dominant HSG cells). Conclusion: Phosphorylation of Ser727 in STAT1 might be more important in IFN[gamma] signaling and the induction of apoptosis in HSG cells than phosphorylation of Tyr701. Accordingly, we propose that phosphorylation of Ser727 in STAT1 could be a potentially suitable new therapeutic target for SS patients to prevent the destruction of salivary glands. [PUBLICATION ABSTRACT]