Cytokines and type 1 diabetes: Role of cytokine mediated signal transduction pathways in pancreatic beta cell dysfunction

Christopher Major, University of Pennsylvania

Abstract

Type 1 diabetes is characterized by an absolute insulin deficiency resulting from the chronic and progressive destruction of pancreatic β-cells by cells of the immune system. In humans as well as animal models, pancreatic islet infiltration by macrophages and lymphocytes, insulitis , precedes β-cell destruction and overt disease development. The final cytotoxic events mediating β-cell destruction in type 1 diabetes may involve a variety of immune/inflammatory cells and products of these activated cells. Correlation studies between cytokines expressed in islets and autoinimune diabetes development in animal models suggest β-cell destruction is associated with increased TH 1 and pro-inflammatory cytokines. The pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α TNF-α and interferon-γ IFN-γ have dramatic effects on pancreatic β-cells in vitro . This study examined the contribution of sphingomyelin and MAP kinase signaling cascades in cytokine mediated β-cell dysfunction using a cultured β-cell model. Treatment of β-cells with cell permeable ceramide analogues decreased both insulin secretion and cell viability mimicking the reported effects of pro-inflammatory cytokines on β-cells However, IL-1β, TNF-α and IFN-γ failed to induce sphingomyelin hydrolysis and ceramide accumulation, suggesting that ceramide does not play a physiologic role in cytokine mediated β-cell dysfunction. However, IL-1β stimulated c-Jun N-terminal kinase (JNK) and p38 MAPK in cultured β-cells, while TNF-α and IFN-γ were without effect, implicating MAPK cascades in IL-1β signaling in β-cells. Further, JNK associated with the JNK interacting protein (JIP) in β-cell lines, suggesting kinase activity may be regulated. Finally, JNK activity was targeted to cytosolic and membrane fractions in β-cells with absolute nuclear exclusion. These finding suggest that JNK mediates a sub-set of IL-1β signals, and further, that JNK activity may be directed to cytosolic or membrane associated substrates as opposed to effects on nuclear activity.

Recommended Citation

Christopher Major, "Cytokines and type 1 diabetes: Role of cytokine mediated signal transduction pathways in pancreatic beta cell dysfunction" (January 1, 2000). Dissertations from ProQuest. Paper AAI9989622.
http://repository.upenn.edu/dissertations/AAI9989622