The BCR/ABL tyrosine kinase inhibitor, nilotinib, stimulates expression of IL-1β in vascular endothelium in association with downregulation of miR-3p. (July 2017)

• Record Type: Journal Article
• Authors: Sukegawa, Masumi; Wang, Xiangmin; Nishioka, Chie; Pan, Bin; Xu, Kailin; Ohkawara, Hiroshi; Hamasaki, Yoichi; Mita, Masayuki; Nakamura, Kenichi; Okamoto, Masatoshi; Shimura, Hiromi; Ohta, Masatsugu; Ikezoe, Takayuki
• Is Part Of: Leukemia research. Volume 58(2017:Jul.)
• Page Start: 83
• Page End: 90
• Publication Date: 2017-07
• Subjects: ABL tyrosine kinase inhibitor -- Endothelial cell damage -- microRNA -- Inflammatory cytokines; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2017.05.005
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: Nilotinib induces expression of IL-1β by vascular endothelial cells. Nilotinib downregulates expression of miR-3121-3p, leading to upregulation of IL-1β. Nilotinib induces expression of adhesion molecules by vascular endothelial cells. Nilotinib stimulates adhesion of monocytes onto vascular endothelial cells. Elevated levels of IL-1β were noted in CML patients who receive nilotinib. Abstract: BCR/ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis for in dividuals with chronic myeloid leukemia (CML). However, many patients treated with TKIs suffer from TKI-related complications. In particular, vascular events such as peripheral artery occlusive disease have become aserious clinical problem for patients who receive the TKI, nilotinib. At present, the molecular mechanisms by which TKIs cause vascular endothelial cell insults remain unknown.This study explored the effects of the TKIs, imatinib, nilotinib and dasatinib, on vascular endothelial cells in vitro, and found that only nilotinib induced expression of interleukin-1β ( IL-1β ) by vascular endothelial cells. Nilotinib-induced IL-1β expression stimulated the adhesion of monocytes to vascular endothelial cells in association with an increase in levels of adhesion molecules. MicroRNA database searching identified miR-3121-3p binding sites in the 3′-UTR of the IL-1β gene. Exposure of endothelial cells to nilotinib caused downregulation of miR-3121-3p in these cells. Importantly, forced-expression of miR-3121-3p counteracted nilotinib-induced expression of IL-1β . Importantly, serum levels if IL-1β were significantly elevated in CML patients receiving nilotinib (n = 14) compared to those receiving other TKIs (n = 16) (3.76 ± 1.22 pg/ml vs 0.27 ± 0.77 pg/ml, p < 0.05). Taken together, our data suggest that nilotinib decreases levels of miR-3121-3p resulting in an increase in expression of IL-1β and adhesion molecules in vascular endothelial cells. The miR-3121-3p/ IL-1β axis could be a potential target to prevent vascular events in CML patients with high risk of vascular events.