Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Fas^lprmice 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.

Radioprotective Effect of Epigallocatechin-3-Gallate on Salivary Gland Dysfunction After Radioiodine Ablation in a Murine Model

“…Dickinson et al [25] showed that EGCG is able to restore the levels of antioxidant defense enzymes providing protection to the salivary glands from oxidative damage in nonobese diabetic mice and human salivary gland cell. Saito et al [26] also demonstrated that EGCG administration to this murine model protects salivary glands from oxidative stress-induced tissue injury. That is, EGCG-mediated increased expression of antioxidants and reduced expression of autoantigens play an important role in the protection of salivary glands against oxidative stress-induced DNA damage and apoptosis in autoimmune sialadenitis of mice [26].…”

“…Saito et al [26] also demonstrated that EGCG administration to this murine model protects salivary glands from oxidative stress-induced tissue injury. That is, EGCG-mediated increased expression of antioxidants and reduced expression of autoantigens play an important role in the protection of salivary glands against oxidative stress-induced DNA damage and apoptosis in autoimmune sialadenitis of mice [26]. …”

A comprehensive review of the influence of Epigallocatechin gallate on Sjögren's syndrome associated molecular regulators of exocytosis (Review)

“…The prevalence of SS seems to be higher in the US population compared to the Japanese and Chinese population ( 21 , 22 ). It was reported that apoptosis, cytotoxicity and autoantigen expression ( 23 ), as well as oxidative stress ( 24 ), all of which are involved in SS pathogenesis and the primary cellular mechanisms underlying its development, are inhibited by GTPs ( 19 , 25 , 26 ).…”

Paradoxical cardiotoxicity of intraperitoneally-injected epigallocatechin gallate preparation in diabetic mice

“…Hyperglycemia is known to aggravate intracellular reactive oxygen species (ROS) formation which induces inflammation and eventually apoptosis 4 . Most of the potential health benefits associated with green tea consumption have been linked to epigallocatechin-3-gallate (EGCG), a major catechin found in green tea 5 . EGCG exhibits anti-oxidant, anti-inflammatory and anti-apoptotic potentials 6 – 8 .…”