PMID- 12540607
OWN - NLM
STAT- MEDLINE
DCOM- 20030407
LR  - 20190516
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 52
IP  - 2
DP  - 2003 Feb
TI  - Molecular regulation of monocyte chemoattractant protein-1 expression in 
      pancreatic beta-cells.
PG  - 348-55
AB  - 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.
FAU - Kutlu, Burak
AU  - Kutlu B
AD  - Laboratory of Experimental Medicine, Universite Libre de Bruxelles, Belgium.
FAU - Darville, Martine I
AU  - Darville MI
FAU - Cardozo, Alessandra K
AU  - Cardozo AK
FAU - Eizirik, Decio L
AU  - Eizirik DL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (DNA Primers)
RN  - 0 (NF-kappa B)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Repressor Proteins)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Binding Sites
MH  - Chemokine CCL2/*genetics
MH  - Chemokines/genetics
MH  - DNA Primers
MH  - *Gene Expression Regulation/*physiology
MH  - Islets of Langerhans/*physiology
MH  - Mutagenesis, Site-Directed
MH  - NF-kappa B/metabolism
MH  - Polymerase Chain Reaction
MH  - *Promoter Regions, Genetic
MH  - Rats
MH  - Recombinant Proteins/metabolism
MH  - Repressor Proteins/metabolism
EDAT- 2003/01/24 04:00
MHDA- 2003/04/08 05:00
CRDT- 2003/01/24 04:00
PHST- 2003/01/24 04:00 [pubmed]
PHST- 2003/04/08 05:00 [medline]
PHST- 2003/01/24 04:00 [entrez]
AID - 10.2337/diabetes.52.2.348 [doi]
PST - ppublish
SO  - Diabetes. 2003 Feb;52(2):348-55. doi: 10.2337/diabetes.52.2.348.