Cytokines and type 1 diabetes : role of cytokine mediated signal transduction pathways in pancreatic beta cell dysfunction / Christopher Major.

Major, Christopher.
xi, 109 p. : ill. ; 29 cm.
Medical subjects:
Dissertations, Academic.
Local subjects:
Penn dissertations -- Pathology. (search)
Pathology -- Penn dissertations. (search)
Type 1 diabetes is characterized by an absolute insulin deficiency resulting from the chronic and progressive destruction of pancreatic beta-cells by cells of the immune system. In humans as well as animal models, pancreatic islet infiltration by macrophages and lymphocytes, insulitis, precedes beta-cell destruction and overt disease development. The final cytotoxic events mediating beta-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 beta-cell destruction is associated with increased TH1 and pro-inflammatory cytokines. The pro-inflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha TNF-alpha and interferon-gamma IFN-gamma have dramatic effects on pancreatic beta-cells in vitro. This study examined the contribution of sphingomyelin and MAP kinase signaling cascades in cytokine mediated beta-cell dysfunction using a cultured beta-cell model. Treatment of beta-cells with cell permeable ceramide analogues decreased both insulin secretion and cell viability mimicking the reported effects of pro-inflammatory cytokines on beta-cells However, IL-1beta, TNF-alpha and IFN-gamma failed to induce sphingomyelin hydrolysis and ceramide accumulation, suggesting that ceramide does not play a physiologic role in cytokine mediated beta-cell dysfunction. However, IL-1beta stimulated c-Jun N-terminal kinase (JNK) and p38 MAPK in cultured beta-cells, while TNF-alpha and IFN-gamma were without effect, implicating MAPK cascades in IL-1beta signaling in beta-cells. Further, JNK associated with the JNK interacting protein (JIP) in beta-cell lines, suggesting kinase activity may be regulated. Finally, JNK activity was targeted to cytosolic and membrane fractions in beta-cells with absolute nuclear exclusion. These finding suggest that JNK mediates a sub-set of IL-1beta signals, and further, that JNK activity may be directed to cytosolic or membrane associated substrates as opposed to effects on nuclear activity.
Supervisor: Bryan A. Wolf.
Thesis (Ph.D. in Pathology) -- University of Pennsylvania, 2000.
Includes bibliographical references.
Local notes:
University Microfilms order no.: 9989622.
Wolf, Bryan A., advisor.
University of Pennsylvania.
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