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

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

Inflammatory Response in Islet Transplantation

Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation