Title: Proteomics analysis of cytokine-induced dysfunction and death in insulin producing INS-1E cells: new insights into the pathways involved
Authors: D'Hertog, Wannes *
Overbergh, Lutgart * ×
Lage, Kasper
Ferreira, Gabriela B
Maris, Michael
Gysemans, Conny
Flamez, Daisy
Cardozo, Alessandra Kupper
Van den Bergh, Gert
Schoofs, Liliane
Arckens, Lut
Moreau, Yves
Hansen, Daniel Aaen
Eizirik, Decio Laks
Waelkens, Etienne
Mathieu, Chantal #
Issue Date: Dec-2007
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Molecular & Cellular Proteomics vol:6 issue:12 pages:2180-2199
Abstract: Cytokines released by islet infiltrating immune cells play a crucial role in ss-cell dysfunction and apoptotic cell death in the pathogenesis of type 1 diabetes. RNA studies revealed complex pathways of genes being activated or suppressed during this ss-cell attack. The aim of the present study was to analyze protein changes in insulin-producing INS-1E cells exposed to inflammatory cytokines in vitro using 2D-DIGE. Within two different pH ranges we observed 2214 +/-164 (pH 4-7) and 1641 +/-73 (pH 6-9) spots. Analysis at 3 different time points (1, 4 and 24 hours of cytokine exposure) revealed that the major changes were taking place only after 24 hours. At this time point 158 proteins were altered in expression (4.1%, n=4, p=0.01) by a combination of IL-1b and IFN-g, whereas only 42 and 23 proteins were altered by either of the cytokines alone, giving rise to 199 distinct differential expressed spots. Identification of 141 of these by MALDI-TOF/TOF, revealed proteins playing a role in insulin secretion, cytoskeleton organization, protein and RNA metabolism, as well as proteins associated with endoplasmic reticulum- and oxidative stress / defense. We investigated the interactions of these proteins and discovered a significant interaction network (p<1.27e-05) containing 42 of the identified proteins. This network analysis suggests that proteins of different pathways act coordinately in a ss-cell dysfunction / apoptotic ss-cell death - interactome. In addition the data suggest a central role for chaperones and proteins playing a role in RNA metabolism. As many of these identified proteins are regulated at the protein level or undergo post-translational modifications, a proteomic approach, as performed in this study, is required to provide adequate insight into the mechanisms leading to ss-cell dysfunction and apoptosis. The present findings may open new avenues for the understanding and prevention of ss-cell loss in type 1 diabetes.
ISSN: 1535-9476
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
Animal Physiology and Neurobiology Section - miscellaneous
ESAT - STADIUS, Stadius Centre for Dynamical Systems, Signal Processing and Data Analytics
Biochemistry Section (Medicine) (-)
Molecular Virology and Gene Therapy
Laboratory of Protein Phosphorylation and Proteomics
Laboratory of Phosphoproteomics (-)
* (joint) first author
× corresponding author
# (joint) last author

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