Sjogren's syndrome (SS) is a complex autoimmune disorder causing dysfunction of the salivary and lacrimal glands, leading to dry mouth and dry eyes. SS is also associated with rheumatic disorders such as rheumatoid arthritis. The cause of SS is unknown and there is no cure;only supportive therapies are available. We recently discovered that green tea polyphenols (GTPs) reduced the severity of autoimmune-induced damage in the salivary glands of a murine model (NOD/Lt) for type I diabetes and SS. Our results from a pilot study indicate that EGCG suppresses the expression of ductal epithelial proliferating cell nuclear antigen (PCNA) and Ki- 67, markers for cell proliferation, starting at early age prior to disease onset. Also, our proteomic and mass spectrometry identified that EGCG normalized several proteins involving in SS and antioxidant activity. These effects are associated with significantly delayed onset of autoimmune diseases. This pres the expression of genes associated with antioxidant and cell proliferation via the MAPK pathways in the salivary gland cells prior to autoimmune activity (when animals are considered healthy), results in delayed onset and reduced severity of SS-like disease in a mouse model for human SS. To test our hypothesis, we designed a variety of experiments to determine the effects of EGCG on early pathological changes associated with the onset of SS-like disease in NOD.B10.H2b mice;and to elucidate the molecular mechanisms associated with EGCG-mediated regulation in salivary gland epithelial cells using both ex vivo and in vitro models. Testing our novel hypotheses will identify candidate strategies for protecting human salivary (and lacrimal) tissue from the effect of SS, and by elucidating the mode of action of EGCG will provide the foundation for the development of novel pharmacological agents to treat and prevent this disease. Information obtained from this proposal will also provide epithelial cells play a key role in both the onset and continuation of this autoimmune disorder. Green tea polyphenol EGCG could normalize early abnormal alterations, prior to autoimmune reaction, in the salivary epithelial cells and may serve as a non-toxic pharmacological agent for early intervention and prevention.
Sj?gren's syndrome (SS) affects 1-3% of the population in the United States. Progression of SS could lead to oral and ocular complications, and significant reduction of the quality of life. The pathogenesis of SS is poorly understood, which made it extremely difficult for prevention and intervention. It is hypothesized that the salivary gland epithelial cells play a key role in both the onset and continuation of this autoimmune disorder. Green tea polyphenol EGCG could normalize early abnormal alterations, prior to autoimmune reaction, in the salivary epithelial cells and may serve as a non-toxic pharmacological agent for early intervention and prevention.
|Dickinson, Douglas; DeRossi, Scott; Yu, Hongfang et al. (2014) Epigallocatechin-3-gallate modulates anti-oxidant defense enzyme expression in murine submandibular and pancreatic exocrine gland cells and human HSG cells. Autoimmunity 47:177-84|
|Dickinson, Douglas; Yu, Hongfang; Ohno, Seiji et al. (2014) Epigallocatechin-3-gallate prevents autoimmune-associated down- regulation of p21 in salivary gland cells through a p53-independent pathway. Inflamm Allergy Drug Targets 13:15-24|