title: Epigallocatechin gallate stimulates the neuroreactive salivary secretomotor system in autoimmune sialadenitis of MRL-Fas(lpr) mice via activation of cAMP-dependent protein kinase A and inactivation of nuclear factor κB.
abstract: The water channel aquaporin 5 (AQP5) plays a crucial role in regulating salivary flow rates. Xerostomia is often observed in patients with Sjögren'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 κB (NF-κB) have been found to be negative regulators of AQP5 expression in the salivary gland. Anti-M3R autoantibodies desensitize M3R to salivary secretagogues in Sjögren's syndrome, while activated NF-κB 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 Sjögren's syndrome. Reactive oxygen species (ROS) can activate NF-κB 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-κB p65 subunit, activated PKA, activated c-Jun N-terminal kinase (JNK) (an activator of NF-κB), inhibitor κB (IκB) and histone deacetylase 1 (HDAC1) (an inhibitor of NF-κB). 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, IκB and HDAC1 were highly expressed in salivary gland tissues, whereas the expression of JNK and NF-κB 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-κB, while IκB and HDAC1 played a pivotal role in the induction of AQP5 expression by PKA. Our study indicates that EGCG may have therapeutic potential for Sjögren's syndrome patients.
authors.affiliation: a Liaison Centre for Innovative Dentistry, Tohoku University Graduate School of Dentistry , Sendai , Japan .
authors.forename: Keiichi
authors.initials: K
authors.lastname: Saito
authors.forename: Shiro
authors.initials: S
authors.lastname: Mori
authors.forename: Fumiko
authors.initials: F
authors.lastname: Date
authors.forename: Guang
authors.initials: G
authors.lastname: Hong
mesh_terms: D000818:Animals; D051402:Aquaporin 5 / Q000235:genetics / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016328:NF-kappa B / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects*; D012793:Sialadenitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013363:Submandibular Gland / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D051402:Aquaporin 5; D016328:NF-kappa B; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D002392:Catechin; C045651:epigallocatechin gallate; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D056284:Histone Deacetylase 1
keywords: HDAC1; IκB; JNK NF-κB; PKA catalytic subunit; Sjögren's syndrome; aquaporin 5