ABSTRACT
Activins regulate the growth and differentiation of a variety of cells. During pancreatic islet development, activins are required for the specialization of pancreatic precursors from the gut endoderm during midgestation. In this study, we probed the role of activin signaling during pancreatic islet cell development and regeneration. Indeed, we found that both activins and activin receptors are upregulated in duct epithelial cells during islet differentiation. Interestingly, the expression of endogenous cellular inhibitors of activin signaling, follistatin and Cripto, were also found to be augmented. Inhibition of activins significantly enhanced survival and expansion of pancreatic epithelial cells but decreased the numbers of differentiated beta-cells. Our results suggest that the homeostasis of growth and terminal differentiation requires a precise context-dependent regulation of activin signaling. Follistatin participates in this process by promoting expansion of precursor cells during pancreas growth.
Subject(s)
Activins/physiology , Epithelial Cells/cytology , Islets of Langerhans/physiology , Pancreas/cytology , Activin Receptors/physiology , Activins/antagonists & inhibitors , Activins/pharmacology , Animals , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Division/drug effects , Cell Division/physiology , Epithelial Cells/drug effects , Follistatin/pharmacology , Humans , Interferon-gamma/genetics , Islets of Langerhans/drug effects , Mice , Mice, Inbred NOD , Mice, Transgenic , Recombinant Proteins/pharmacologyABSTRACT
The mechanisms that regulate susceptibility to virus-induced autoimmunity remain undefined. We establish here a fundamental link between the responsiveness of target pancreatic beta cells to interferons (IFNs) and prevention of coxsackievirus B4 (CVB4)-induced diabetes. We found that an intact beta cell response to IFNs was critical in preventing disease in infected hosts. The antiviral defense, raised by beta cells in response to IFNs, resulted in a reduced permissiveness to infection and subsequent natural killer (NK) cell-dependent death. These results show that beta cell defenses are critical for beta cell survival during CVB4 infection and suggest an important role for IFNs in preserving NK cell tolerance to beta cells during viral infection. Thus, alterations in target cell defenses can critically influence susceptibility to disease.