Cytokine signaling in the pancreatic beta-cell

Type I diabetes occurs when immune cells, such as macrophages, infiltrate the pancreatic islets of Langerhans and release cytokines, which mediate the destruction of the islet beta-cells. One of these cytokines, IL-1beta, causes multiple deleterious effects, including the release of inflammatory mediators such as NO, ultimately culminating in beta-cell death. However, the exact signaling pathway(s) involved in cytokine induced beta-cell death is not yet known, making prevention very difficult. Previous studies have implicated small G-proteins in the pathway leading to NO release in pancreatic beta-cells. One of the steps involved in G-protein activation is the post-translational modification, farnesylation. The current work has used specific inhibitors of farnesylation as well as molecular biological approaches to knock-down the enzyme responsible to conclude that farnesylation is involved in IL-1beta mediated NO release.;A second post-translational modification that has been shown to be important for NO release in other cell types is the acetylation of histone proteins. Using various pharmacological inhibitors, this work demonstrates that HDACs play a role in IL-1beta induced beta-cell death. We also show that inhibition of HDACs using novel HDAC inhibitors can prevent IL-1beta induced NO release and subsequent beta-cell death. These novel HDAC inhibitors are not cytotoxic to the beta-cells because they are more isoform specific than previous HDAC inhibitors. However, to improve these inhibitors further, the particular HDACs involved in IL-1beta mediated NO release need to be known, so we used siRNA to knock-down various HDAC isoforms and determined that HDACs 1 and 2 are involved in NO release in beta-cells.;Lastly, this work demonstrates the involvement of PKCdelta in IL-1beta induced iNOS expression and NO release. It has previously been shown that IL-1beta activates PKCdelta and that PKCdelta can stabilize iNOS mRNA. Here, we determined that inhibition of PKCdelta can also result in an increase in histone H4 acetylation and thereby inhibiting iNOS expression. Although this novel effect of PKCdelta is not due to inhibition of HDACs, it has been shown that PKCdelta can phosphorylate and thereby inactivate HATs in other cell types, which may be the case in beta-cells as well.