RGD Reference Report - Molecular regulation of monocyte chemoattractant protein-1 expression in pancreatic beta-cells. - Rat Genome Database

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Molecular regulation of monocyte chemoattractant protein-1 expression in pancreatic beta-cells.

Authors: Kutlu, B  Darville, MI  Cardozo, AK  Eizirik, DL 
Citation: Kutlu B, etal., Diabetes 2003 Feb;52(2):348-55.
RGD ID: 634051
Pubmed: PMID:12540607   (View Abstract at PubMed)

Pancreatic beta-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 beta-cells, insulin-producing INS-1E cells, and RINm5F cells was investigated. Transient transfections with luciferase-reporter constructs identified an interleukin (IL)-1beta-responsive enhancer region between -2,180 bp and -2,478 bp. Mutation of either of the two nuclear factor (NF)-kappaB sites present in this region abrogated IL-1beta-induced MCP-1 promoter activity. Binding of NF-kappaB 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-kappaB was confirmed by chromatin immunoprecipitation assay. Blocking of NF-kappaB activation in cytokine-exposed primary beta-cells by an adenovirus overexpressing a nondegradable form of IkappaBalpha or by pyrrolidine dithiocarbamate decreased IL-1beta-induced MCP-1 mRNA expression. We conclude that NF-kappaB plays an important role for MCP-1 expression in beta-cells. This transcription factor may be an interesting target for ex vivo gene therapy before islet transplantation.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
chemokinesis  TAS 634051 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
chemokine activity  TAS 634051 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccl2  (C-C motif chemokine ligand 2)

Additional Information