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https://hdl.handle.net/2440/57596
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Type: | Journal article |
Title: | Dasatinib inhibits the secretion of TNF-α following TLR stimulation in vitro and in vivo |
Other Titles: | Dasatinib inhibits the secretion of TNF-alpha following TLR stimulation in vitro and in vivo |
Author: | Fraser, C. Lousberg, E. Kumar, R. Hughes, T. Diener, K. Hayball, J. |
Citation: | Experimental Hematology, 2009; 37(12):1435-1444 |
Publisher: | Elsevier Science Inc |
Issue Date: | 2009 |
ISSN: | 0301-472X 1873-2399 |
Statement of Responsibility: | Cara K. Fraser, Erin L. Lousberg, Raman Kumar, Timothy P. Hughes, Kerrilyn R. Diener and John D. Hayball |
Abstract: | <h4>Objective</h4>Dasatinib (SPRYCEL, BMS-354825) is a small molecule Src/Abl tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, kinases inhibited by dasatinib are also involved in the induction and regulation of innate immunity. The purpose of this study was to evaluate the effect of dasatinib on cytokine secretion in response to toll-like receptor (TLR) stimulation.<h4>Materials and methods</h4>Dasatinib-treated mice were administered intraperitoneally with lipopolysaccharide (LPS) and serum cytokine (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-10, and IL-6) levels and neutrophil accumulation in the lungs were analyzed. Cytokine secretions (TNF-alpha and IL-6) from TLR3-, TLR4-, and TLR9-stimulated RAW264.7, as well as TLR4- and TLR9-stimulated bone marrow-derived macrophages (BMDM) were also evaluated.<h4>Results</h4>Dasatinib-treated mice had reduced serum levels of TNF-alpha in response to LPS administration; however, other inflammatory hallmarks of systemic LPS administration, such as secretion of IL-6 and accumulation of neutrophils in the lung, were unaffected. In contrast to the reduced TNF-alpha levels, dasatinib treatment increased serum levels of IL-10 following LPS administration. The production of TNF-alpha was also impaired in vitro in response to TLR3, TLR4, and TLR9 stimulation of the mouse macrophage cell line RAW264.7, as well as TLR4 and TLR9 stimulation of BMDM; IL-6 production was also impaired in dasatinib-treated BMDM.<h4>Conclusions</h4>These findings further support the ability of dasatinib to modulate the host immune response and highlights scope for off-target applications of dasatinib for the control of TNF-alpha-mediated inflammatory disorders. |
Keywords: | Lung Neutrophils Bone Marrow Cells Cells, Cultured Cell Line Macrophages Animals Mice, Inbred Strains Mice, Inbred C57BL Mice Pyrimidines Thiazoles Lipopolysaccharides Tumor Necrosis Factor-alpha Interleukin-6 Interleukin-10 Enzyme-Linked Immunosorbent Assay Injections, Intraperitoneal Dose-Response Relationship, Drug Toll-Like Receptors Toll-Like Receptor 3 Toll-Like Receptor 4 Toll-Like Receptor 9 Dasatinib |
Rights: | Copyright © 2009 Elsevier Ltd All rights reserved |
DOI: | 10.1016/j.exphem.2009.09.007 |
Published version: | http://dx.doi.org/10.1016/j.exphem.2009.09.007 |
Appears in Collections: | Aurora harvest Medicine publications |
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