Sjögren's syndrome (SS) is characterized by autoimmune activation and loss of function in the salivary glands. Recent studies reported that bone morphogenetic protein 6 (BMP6), which is a member of transforming growth factor beta (TGF-β) superfamily, was highly expressed in SS patients. To investigate the role of BMP6 in SS, we treated the salivary gland-derived mesenchymal stem cells (SGMSCs) with BMP6 and found that BMP6 could impair immunomodulatory properties of normal SGMSCs by downregulating the Prostaglandin E2 synthase through DNA-binding protein inhibitor-1. Neutralizing the BMP6 could significantly restore the SGMSC's immunoregulatory function in vitro and delay the SS disease activity in vivo. In conclusion, BMP6 could not only affect the secreting function of epithelial cells in the salivary gland but also influence the immunomodulatory properties of SGMSCs, which may trigger or enhance the autoimmune reflection in SS.