Epigallocatechin gallate stimulates the neuroreactive salivary secretomotor system in autoimmune sialadenitis of MRL-Faslpr mice via activation of cAMP-dependent protein kinase A and inactivation of nuclear factor κB

The water channel aquaporin 5 (AQP5) plays a crucial role in regulating salivary flow rates. Xerostomia is often observed in patients with Sjogren's syndrome, and this is attributed to reduced AQP5 expression in the salivary glands. Recently, anti-type 3 muscarinic cholinergic receptors (M3R) autoantibodies and nuclear factor kappa B (NF-kappa B) have been found to be negative regulators of AQP5 expression in the salivary gland. Anti-M3R autoantibodies desensitize M3R to salivary secretagogues in Sjogren's syndrome, while activated NF-kappa B translocates to nuclei and binds to the AQP5 gene promoter, resulting in the suppression of AQP5 expression. We previously documented that epigallocatechin gallate (EGCG), which is a robust antioxidant contained in green tea, ameliorates oxidative stress-induced tissue damage to the salivary glands of MRL/MpJ-lpr/lpr (MRL-Fas(lpr)) mice, which are widely used as a model of Sjogren's syndrome. Reactive oxygen species (ROS) can activate NF-kappa B and inactivate protein kinase A (PKA), which is a key driver of AQP5 expression. In this study, we examined the effects of administering EGCG to MRL-Fas(lpr) mice with autoimmune sialadenitis on the levels of AQP5, activated NF-kappa B p65 subunit, activated PKA, activated c-Jun N-terminal kinase (JNK) (an activator of NF-kappa B), inhibitor kappa B (I kappa B) and histone deacetylase 1 (HDAC1) (an inhibitor of NF-kappa B). In EGCG-treated mice, intense aster-like immunostaining for AQP5 was observed on the apical plasma membranes (APMs) of submandibular gland acinar cells. Likewise, PKA, I kappa B and HDAC1 were highly expressed in salivary gland tissues, whereas the expression of JNK and NF-kappa B p65 was negligible. Rank correlation and partial correlation analyses revealed that treatment with EGCG upregulated AQP5 expression on the APM of acinar cells through activation of PKA and inactivation of NF-kappa B, while I kappa B and HDAC1 played a pivotal role in the induction of AQP5 expression by PKA. Our study indicates that EGCG may have therapeutic potential for Sjogren's syndrome patients.