nPOD. Beta Cell Physiology and Dysfunction

The role inflammatory signaling crosstalk on human exocrine and beta cells

There is increasing evidence for cross-talk between the islet and exocrine compartments of the pancreas. Diabetes is a risk factor for exocrine atrophy, pancreatitis, and pancreatic cancer. Conversely, pancreatitis is a risk factor for diabetes. Until now our ability to study human endocrine and exocrine cells has been limited to isolated islets and isolated exocrine tissue. The tissue slice program provides a unique opportunity to simultaneously examine the immediate effects of exposure to inflammatory associated with diabetogenic or pancreatitis on both human beta cell and exocrine cell physiology. Here we will treat pancreas slices with the exocrine inflammatory molecule caerulein or the diabetogenic cytokines IL1beta and IFNgamma, measuring cell function and stress in both compartments. We previously showed that short term treatment of isolated exocrine cultures with caerulein induced BMP signaling, the transcriptional repressors ID1 and ID3 that promoted a potent proliferative response, as well as expression of inflammatory cytokines that may affect islets (Lee et. al. 2011a). In contrast to exocrine cells, human islets responded to ID3 with replication stress and DNA damage (Lee et. al 2011b). We also recently profiled gene expression in human islets exposed to a cytokine cocktail of IL1beta and IFNgamma, finding that the islets underwent ER stress and were induced to express chemokines that may well impact neighboring exocrine cells. In summary, the pancreas slice program enables the study of human endocrine/exocrine cross-talk in tissue for the first time.

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