(Journal Article): A choice of death - the signal-transduction of immune-mediated beta-cell apoptosis.
 
Eizirik DL, Mandrup-Poulsen T (Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, Belgium., deizirik@mebo.vub.ac.be )
 
IN: Diabetologia 2001; 44(12):2115-2133
Impact Factor(s) of Diabetologia: 5.583 (2004), 5.689 (2003), 5.136 (2002), 6.299 (2001)

Fulltext:    HTML  PDF

ABSTRACT: Apoptosis is likely to be the main form of beta-cell death in immune-mediated diabetes mellitus in rodents and possibly in humans. Clarification of the regulation of beta-cell death could indicate novel sites for therapeutic intervention in Type I (insulin-dependent) diabetes mellitus. We review the molecular effectors and signal transduction of immune-mediated beta-cell apoptosis. Data obtained on non-obese diabetic (NOD) mice suggest that macrophages and CD4+ T-cells are the main cellular effectors, whereas CD8+ T-cells are more important initiators of the immune process leading to beta-cell death. Perforin could be the effector molecule utilized by CD8+ T-cell initiation, whereas CD4+ mediated beta-cell destruction is mostly dependent on Fas/FasL and the cytokines IFNgamma and TNF-alpha. The macrophage cytokine IL-1beta in combination with IFN-gamma and TNF-alpha, plays an important role for beta-cell dysfunction and death. Signal transduction by these cytokines involves: (i) binding to specific receptors, (ii) signal transduction by cytosolic kinases (especially the so-called mitogen- and stress-activated protein kinases) and/or phosphatases, (iii) mobilization of diverse transcription factors - with nuclear factor kappaB (NF-kappaB), AP-1 and STAT-1 probably playing key roles for beta-cell apoptosis; (iv) up-regulation or down-regulation of gene transcription. Recent data obtained by microarray and proteomic analysis suggest that the process of beta-cell apoptosis depends on the parallel and/or sequential up-regulation and down-regulation of considerable numbers of genes, which can be grouped in gene modules or patterns according to their functions. A detailed characterization of these "gene modules", and of the signalling pathways and transcription factors regulating them could allow us to understand the ultimate mechanisms leading to beta-cell apoptosis.

TYPE OF PUBLICATION: Review

Articles citing this article:

• Sia C. Is a New Immune Response Mediator in the NF-κB pathway - SUMO-4 - Related to Type 1 Diabetes? Rev Diabetic Stud 2005. 2: 58-60.
  » Diabetes OD » Diabetes Pathogenesis » T1DM » Autoimmunity » Genetics of Autoimmunity » SUMO4 » Journal Article