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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.
AuthorsKeiichi Saito, Shiro Mori, Fumiko Date, Masao Ono
JournalAutoimmunity (Autoimmunity) Vol. 47 Issue 1 Pg. 13-22 (Feb 2014) ISSN: 1607-842X [Electronic] England
PMID24392721 (Publication Type: Journal Article)
Chemical References
  • Antioxidants
  • Autoantigens
  • Proto-Oncogene Proteins c-bcl-2
  • Catechin
  • epigallocatechin gallate
  • Heme Oxygenase-1
Topics
  • Animals
  • Antioxidants (administration & dosage, pharmacology)
  • Apoptosis (drug effects, genetics)
  • Autoantigens (genetics, immunology, metabolism)
  • Autoimmune Diseases (genetics, immunology, pathology)
  • Catechin (administration & dosage, analogs & derivatives, pharmacology)
  • DNA Damage (drug effects)
  • Disease Models, Animal
  • Gene Expression Regulation (drug effects)
  • Heme Oxygenase-1 (genetics)
  • Mice
  • Mice, Inbred MRL lpr
  • Oxidative Stress (drug effects, genetics)
  • Proto-Oncogene Proteins c-bcl-2 (genetics)
  • Severity of Illness Index
  • Sialadenitis (genetics, immunology, pathology)
  • Submandibular Gland (immunology, metabolism, pathology)

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