Use of microarray analysis to unveil transcription factor and gene networks contributing to Beta cell dysfunction and apoptosis.
The beta cell fate following immune-mediated damage depends on an intricate pattern of dozens of genes up- or downregulated in parallel and/or sequentially. We are utilizing microarray analysis to clarify the pattern of gene expression in primary rat beta cells exposed to the proapoptotic cytokines, IL-1beta and/or IFN-gamma. The picture emerging from these experiments is that beta cells are not passive bystanders of their own destruction. On the contrary, beta cells respond to damage by activating diverse networks of transcription factors and genes that may either lead to apoptosis or preserve viability. Of note, cytokine-exposed beta cells produce and release chemokines that may contribute to the homing and activation of T cells and macrophages during insulitis. Several of the effects of cytokines depend on the activation of the transcription factor, NF-kappaB. NF-kappaB blocking prevents cytokine-induced beta cell death, and characterization of NF-kappaB-dependent genes by microarray analysis indicated that this transcription factor controls diverse networks of transcription factors and effector genes that are relevant for maintenance of beta cell differentiated status, cytosolic and ER calcium homeostasis, attraction of mononuclear cells, and apoptosis. Identification of this and additional "transcription factor networks" is being pursued by cluster analysis of gene expression in insulin-producing cells exposed to cytokines for different time periods. Identification of complex gene patterns poses a formidable challenge, but is now technically feasible. These accumulating evidences may finally unveil the molecular mechanisms regulating the beta cell "decision" to undergo or not apoptosis in early T1DM.
Eizirik
Decio L
DL
Laboratory of Experimental Medicine, Université Libre de Bruxelles, B-1070 Brussels, Belgium. deizirik@ulb.ac.be
Kutlu
Burak
B
Rasschaert
Joanne
J
Darville
Martine
M
Cardozo
Alessandra K
AK
D017209:Apoptosis / Q000502:physiology*; D007515:Islets of Langerhans / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D014157:Transcription Factors / Q000502:physiology*
D014157:Transcription Factors