Effects of Imatinib Mesylate (Gleevec) on Human Islet NF-kappaB Activation and Chemokine Production In Vitro
2011 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 9, e24831- p.Article in journal (Refereed) Published
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-kappa B signaling and islet cell survival. The aim of this study was to investigate control of NF-kappa B 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. I kappa B-alpha and NF-kappa B 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 I kappa B-alpha 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 I kappa B-alpha 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-kappa B. However, a prolonged exposure of human islets to Imatinib is associated with a dampened response to cytokines. It is possible that Imatinib induces NF-kappa B preconditioning of islet cells leading to lowered cytokine sensitivity and a mitigated islet inflammation.
Place, publisher, year, edition, pages
2011. Vol. 6, no 9, e24831- p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-159788DOI: 10.1371/journal.pone.0024831ISI: 000295039700053OAI: oai:DiVA.org:uu-159788DiVA: diva2:447061