title: Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Fas(lpr) mice with autoimmune sialadenitis via upregulation of heme oxygenase-1 and Bcl-2.
abstract: Pathogenic effects of reactive oxygen species (ROS) in the salivary glands of patients with Sjögren's syndrome have been demonstrated. Epigallocatechin gallate (EGCG), which is a catechin derivative and exhibits potent antioxidant activity, has been reported to ameliorate autoimmune sialadenitis in a murine model, but the mechanism underlying its protective action remains to be investigated. Herein, we examined the effects of EGCG administration to MRL/MpJ-lpr/lpr (MRL-Fas(lpr)) mice on disease severity of autoimmune sialadenitis and protein expression levels of 11 sialadenitis-related molecules - heme oxygenase-1 (HO-1) (antioxidant); thymidine glycol (marker of DNA damage); gp91phox/NADPH oxidase 2 (prooxidant); single-stranded DNA (ssDNA) and cleaved caspase 3 (apoptotic cell markers); p53 and Bax (proapoptotic molecules); Bcl-2 (antiapoptotic molecule); SSA/Ro, SSB/La, and Ifi202 (autoantigens). In EGCG-treated mice, the severity of sialadenitis was substantially decreased. Expression levels of thymidine glycol, gp91phox, ssDNA, cleaved caspase 3, p53, Bax, SSA/Ro, SSB/La, and Ifi202 in duct epithelial cells of salivary glands from EGCG-treated mice were reduced, whereas HO-1 and Bcl-2 were overexpressed. Results of correlation analysis among sialadenitis severity and 11 sialadenitis related-molecules, and those of partial correlation analysis between apoptotic related-molecules and sialadenitis severity or HO-1 suggested that the consecutive pathogenic cycle including activated autoimmune reactions, ROS synthesis, DNA damage and p53-dependent apoptosis was associated with the pathogenesis of autoimmune sialadenitis in MRL-Fas(lpr) mice. Overexpression of HO-1 and Bcl-2 mediated by EGCG blocked this pathogenic cycle, subsequently resulting in the inhibition of ROS-mediated DNA damage and apoptosis, and protected salivary gland tissues from oxidative stress. Clinically, green tea catechin may have therapeutic efficacy for Sjögren's syndrome.
authors.affiliation: 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: Masao
authors.initials: M
authors.lastname: Ono
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012720:Severity of Illness Index; D012793:Sialadenitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D013363:Submandibular Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D001324:Autoantigens; D019253:Proto-Oncogene Proteins c-bcl-2; D002392:Catechin; C045651:epigallocatechin gallate; D051547:Heme Oxygenase-1