title: Imatinib inhibits the functional capacity of cultured human monocytes.
abstract: Imatinib is a tyrosine kinase inhibitor that has been reported to specifically inhibit the growth of bcr-abl expressing chronic myeloid leukaemia progenitors. This drug functions by blocking the ATP-binding site of the kinase domain of bcr-abl, and has also been found to inhibit the c-abl, platelet-derived growth factor receptor, ARG and stem cell factor receptor tyrosine kinases. Reports have recently emerged demonstrating that imatinib also inhibits the growth of non-malignant haemopoietic cells. Here, we demonstrate that concentrations of imatinib within the therapeutic dose range inhibit the function of cultured monocytes (CM) from normal donors. A decrease in the response of CM to LPS was observed morphologically and functionally, with CM grown in the presence of imatinib showing decreased pseudopodia formation and inhibition of IL-6 and TNF-alpha production following LPS stimulation. Imatinib also reduced the ability of M-CSF and GM-CSF stimulated CM to phagocytose zymosan particles, with uptake of non-opsonized zymosan by M-CSF stimulated CM (M-CM) being most affected. M-CM that had been cultured in the presence of imatinib were also impaired in their ability to stimulate responder cells in a mixed lymphocyte reaction. These results demonstrate that human monocytes cultured in the presence of imatinib are functionally impaired, and suggest that imatinib displays inhibitory activity against other kinase(s) that play a role in monocyte/macrophage development.
authors.affiliation: Division of Haematology, Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia. andrea.dewar@imvs.sa.gov.au
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Dewar
authors.forename: Kathleen V
authors.initials: KV
authors.lastname: Doherty
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: A Bruce
authors.initials: AB
authors.lastname: Lyons
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D018122:B7-1 Antigen / Q000032:analysis; D051940:B7-2 Antigen; D001549:Benzamides; D002478:Cells, Cultured; D006801:Humans; D000068877:Imatinib Mesylate; D008070:Lipopolysaccharides / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000032:analysis; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011554:Pseudopodia / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D001549:Benzamides; D000068877:Imatinib Mesylate; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010879:Piperazines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C497964:CD86 protein, human