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Diabetes 52:348-355, 2003
© 2003 by the American Diabetes Association, Inc.

Molecular Regulation of Monocyte Chemoattractant Protein-1 Expression in Pancreatic ß-Cells

Burak Kutlu1, Martine I. Darville1, Alessandra K. Cardozo1,2, and Décio L. Eizirik1

1 Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
2 Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium

Pancreatic ß-cells are selectively destroyed during the course of type 1 diabetes. In the early stages of the disease, inflammatory infiltrates of mononuclear cells, containing predominantly monocytes and T-cells, are present in the islets (insulitis). Chemokines, such as monocyte chemoattractant protein-1 (MCP-1), play a key role in the recruitment and activation of these immunocytes. We have previously described cytokine-induced MCP-1 gene expression in human and rat pancreatic islets. In the present study, the transcriptional regulation by cytokines of the rat MCP-1 gene in fluorescence-activated cell sorting-purified rat ß-cells, insulin-producing INS-1E cells, and RINm5F cells was investigated. Transient transfections with luciferase-reporter constructs identified an interleukin (IL)-1ß-responsive enhancer region between -2,180 bp and -2,478 bp. Mutation of either of the two nuclear factor (NF)-{kappa}B sites present in this region abrogated IL-1ß-induced MCP-1 promoter activity. Binding of NF-{kappa}B to the two sites was shown in vitro by gel shift assays, while supershift assays revealed the presence of p65/p50 heterodimers and p65 homodimers. In vivo binding of NF-{kappa}B was confirmed by chromatin immunoprecipitation assay. Blocking of NF-{kappa}B activation in cytokine-exposed primary ß-cells by an adenovirus overexpressing a nondegradable form of I{kappa}B{alpha} or by pyrrolidine dithiocarbamate decreased IL-1ß-induced MCP-1 mRNA expression. We conclude that NF-{kappa}B plays an important role for MCP-1 expression in ß-cells. This transcription factor may be an interesting target for ex vivo gene therapy before islet transplantation.


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