Epigallocatechin-3-gallate modulates antioxidant and DNA repair-related proteins in exocrine glands of a primary Sjogren's syndrome mouse model prior to disease onset

Abstract

The autoimmune disorder primary Sjogren's syndrome (SS) is associated with xerostomia and xerophthalmia. SS pathogenesis involves both genetic/epigenetic and environmental factors. A major potential contributor is oxidative stress associated with damage to cellular components, including DNA. We reported previously that the green tea polyphenol epigallocatechin-3-gallate (EGCG) normalizes the elevated levels of proliferating cell nuclear antigen (PCNA), a key component of DNA repair, in the NOD mouse model for SS and type 1 diabetes. The current study examined levels of the antioxidant enzymes peroxiredoxin 6 (PRDX6), catalase and superoxide dismutase (SOD), as well as PCNA, in NOD.B10.Sn-H2 mice, a model for primary SS, and determined the effect of EGCG on their expression. PCNA elevation was detected in the submandibular gland and pancreas by 8 weeks of age in water-fed mice, and increased through 14 weeks of age, prior to overt onset of symptoms. This early PCNA elevation was followed by a decline of peroxiredoxin 6 protein. In contrast, EGCG-fed mice exhibited normal levels of PCNA and peroxiredoxin 6, comparable to healthy untreated BALB/c mice. Similar patterns were observed in the pancreas, even though these mice do not develop diabetes. Thus, elevated PCNA is an early biomarker for exocrine glandular dysfunction associated with SS-like autoimmune disease, accompanied subsequently by decreased PRDX6 antioxidant enzyme levels that could further contribute to oxidative stress, and these changes precede inflammatory cell infiltration. Importantly, EGCG consumption normalizes the expression of these biomarkers in this model. These observations could lead to early diagnosis and intervention of autoimmune disorders.

Epigallocatechin-3-gallate modulates anti-oxidant defense enzyme expression in murine submandibular and pancreatic exocrine gland cells and human HSG cells

“…The majority of this reduction was not due to cytotoxicity, indicating a more complex dose response pattern than simple induction. A down-regulation of PRDX6 was not observed in EGCG-fed animals, consistent with serum levels not reaching inhibitory/non-inducing concentrations (13). …”

“…Previously, we showed that levels of PRDX6 were reduced before those of the other two enzymes (13). This suggests that PRDX6 plays a key role in maintaining the antioxidant capacity in exocrine glands, consistent with a known role in providing defensive activity against oxidative stress (24).…”

“…We and others reported previously that EGCG delayed/prevented the onset of spontaneous insulin-dependent diabetes in NOD mice (12, 21). Previously, we examined levels of antioxidant proteins in the NOD.B10.Sn.H2 mouse, a model for pSS that does not develop diabetes at early time points, before the onset of frank lymphocytic infiltration (13). In the submandibular gland, the levels of PRDX6 (an antioxidant enzyme) began to decline around 10 weeks, and were significantly lower at 14 weeks, but were restored to normal by dietary EGCG.…”

“…Recently, we found that in a mouse model for primary Sjogren’s syndrome (NOD.B10.Sn-H2), peroxiredoxin 6 is significantly decreased in both the salivary gland and pancreas prior to the onset of autoimmune symptoms, and EGCG normalizes the antioxidant defense protein levels (13). However, the mechanism underlying the protective role EGCG plays in these animal models is not clear.…”

Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Faslprmice with autoimmune sialadenitis via upregulation of heme oxygenase-1 and Bcl-2

“…Consequently, these actions facilitate protective efficacy against ROS-induced apoptosis and tissues destruction [23][24][25][26][27][28]. Additionally, EGCG administration to animal models of autoimmune diseases has been reported to mitigate symptoms and improve the pathological features of autoimmune lesions in rheumatoid arthritis [29,30], multiple sclerosis (experimental autoimmune encephalomyelitis in the animal model) [31], type I diabetes [32], lupus nephritis [33], and Sjögren's syndrome [34][35][36]. EGCG administration has been demonstrated to reduce the autoimmune-induced lymphocytic infiltration in the sialadenitis of NOD mice, a murine model of Sjögren's syndrome [36], but the mechanisms of its suppressive and protective actions on ROS-induced tissue injury of salivary glands in this lesion are completely unexplored.…”