Anti-inflammatory effects of withaferin A in islet transplantation and pancreatitis.

Abstract

Islet transplantation is a promising treatment for patients severely affected by type 1 diabetes and chronic pancreatitis. Islets are transplanted into the portal vein of the liver, and direct contact of islets with blood initiates a strong innate immune response called instant blood-mediated inflammation response (IBMIR). Approximately 50% to 60% of islets may be lost during the peritransplant period due to IBMIR. A transcription factor known as nuclear factor kappa B (NFκB) primarily mediates the proinflammatory response in islets. Preliminary studies using withaferin A (WA), a plant-derived inhibitor of NFκB, showed protection of islets from proinflammatory cytokine-mediated damage. An in vitro tube model for IBMIR was developed to determine the inhibitory effect of WA. After transplantation, islet damage was evaluated using C-peptide and proinsulin levels in serum, which are influenced by metabolic stimuli. Identification of a biomarker specific for islet damage uninfluenced by physiological changes is a critical need. MicroRNA 375 is highly expressed in β cells of islets, and damage of islets results in release of this miRNA into the bloodstream. Analysis of serum samples during and after islet infusion revealed high levels of microRNA 375, indicating damage by IBMIR, and the estimated islet loss was comparable to that in previous reports. Serum microRNA 375 was also analyzed to validate the inhibitory effect of WA on IBMIR in vitro. Chronic pancreatitis is an inflammatory disease affecting the exocrine and subsequently endocrine function of the pancreas. Currently, there is no therapeutic approach to delay progression of the disease. The underlying mechanism of pathogenesis of chronic pancreatitis is not clearly understood. The activation of NFκB in acinar cells has been reported to enhance the severity of chronic pancreatitis. NFκB inhibition by WA was tested in a cerulein-induced pancreatitis mouse model. The sustained inflammation that leads to chronic pancreatitis is potentiated by endoplasmic reticulum stress and inflammasome activation within the pancreas. Treatment with WA prevented activation of these mechanisms, as evidenced by molecular analysis and histological assessment. In summary, inhibition of NFκB by WA could be a promising strategy to treat chronic pancreatic diseases.