Format

Send to

Choose Destination
PLoS One. 2011;6(9):e24831. doi: 10.1371/journal.pone.0024831. Epub 2011 Sep 14.

Effects of Imatinib Mesylate (Gleevec) on human islet NF-kappaB activation and chemokine production in vitro.

Author information

1
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. dariush.mokhtari@mcb.uu.se

Abstract

PURPOSE:

Imatinib Mesylate (Gleevec) is a drug that potently counteracts diabetes both in humans and in animal models for human diabetes. We have previously reported that this compound in human pancreatic islets stimulates NF-κB signaling and islet cell survival. The aim of this study was to investigate control of NF-κB post-translational modifications exerted by Imatinib and whether any such effects are associated with altered islet gene expression and chemokine production in vitro.

PROCEDURES:

Human islets were either left untreated or treated with Imatinib for different timepoints. IκB-α and NF-κB p65 phosphorylation and methylation were assessed by immunoblot analysis. Islet gene expression was assessed using a commercial Pathway Finder microarray kit and RT-PCR. Islet chemokine production was determined by flow cytometric bead array analysis.

FINDINGS:

Human islet IκB-α and Ser276-p65 phosphorylation were increased by a 20 minute Imatinib exposure. Methylation of p65 at position Lys221 was increased after 60 min of Imatinib exposure and persisted for 3 hours. Microarray analysis of islets exposed to Imatinib for 4 hours revealed increased expression of the inflammatory genes IL-4R, TCF5, DR5, I-TRAF, I-CAM, HSP27 and IL-8. The islet release of IL-8 was augmented in islets cultured over night in the presence of Imatinib. Following 30 hours of Imatinib exposure, the cytokine-induced IκB-α and STAT1 phosphorylation was abolished and diminished, respectively. The cytokine-induced release of the chemokines MIG and IP10 was lower in islets exposed to Imatinib for 30 hours.

CONCLUSION:

Imatinib by itself promotes a modest activation of NF-κB. However, a prolonged exposure of human islets to Imatinib is associated with a dampened response to cytokines. It is possible that Imatinib induces NF-κB preconditioning of islet cells leading to lowered cytokine sensitivity and a mitigated islet inflammation.

PMID:
21935477
PMCID:
PMC3173488
DOI:
10.1371/journal.pone.0024831
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center