Dasatinib inhibits the secretion of TNF-α following TLR stimulation in vitro and in vivo
Received 23 July 2009; received in revised form 31 August 2009; accepted 22 September 2009. published online 28 September 2009.
Objective
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.
Materials and Methods
Dasatinib-treated mice were administered intraperitoneally with lipopolysaccharide (LPS) and serum cytokine (tumor necrosis factor–α [TNF-α], interleukin [IL]-10, and IL-6) levels and neutrophil accumulation in the lungs were analyzed. Cytokine secretions (TNF-α 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.
Results
Dasatinib-treated mice had reduced serum levels of TNF-α 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-α levels, dasatinib treatment increased serum levels of IL-10 following LPS administration. The production of TNF-α 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.
Conclusions
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-α–mediated inflammatory disorders.
bSansom Institute, The University of South Australia, South Australia, Australia
cSchool of Medicine, The University of Adelaide, South Australia, Australia
dDepartment of Haematology, SA Pathology, South Australia, Australia
Offprint requests to: John D. Hayball, Ph.D., Sansom Institute, The University of South Australia, North Tce, Adelaide, South Australia 5000, Australia
ABSTRACT