Juurikivi, A. et al. Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis. Ann. Rheum. Dis. 64, 1126-1131

University of Helsinki, Helsinki, Uusimaa, Finland
Annals of the Rheumatic Diseases (Impact Factor: 10.38). 09/2005; 64(8):1126-31. DOI: 10.1136/ard.2004.029835
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Mast cells have been implicated in the pathogenesis of arthritis, but elucidation of their precise role has been hampered by a lack of efficient and selective inhibitors of their function.
To elucidate the role of mast cells in the pathogenesis of rheumatoid arthritis (RA) and to assess whether apoptosis of cultured and synovial tissue mast cells can be induced by inhibiting mast cell growth factor receptor, c-kit tyrosine kinase.
Double staining with tumour necrosis factor (TNF) alpha and tryptase antibodies showed the presence of TNFalpha positive mast cells in human rheumatoid synovial tissue. Selective activation of mast cells by anti-IgE resulted in production of TNFalpha in synovial tissue cultures. Inhibition of the c-kit tyrosine kinase with imatinib mesylate (1.0-10 micromol/l) induced profound apoptosis in cultured mast cells as judged by typical apoptotic morphology, increased number of apoptotic nucleosomes, and activation of caspases 8 and 9. Importantly, imatinib also induced apoptosis of mast cells in explant cultures of synovial tissue obtained from patients with RA as judged by a TUNEL assay. Inhibition of c-kit tyrosine kinase was accompanied by significant reduction of TNFalpha production in synovial tissue cultures.
Mast cells may have a role in the pathogenesis of RA, and inhibition of c-kit may be a new means of inhibiting mast cell activity and of abrogating the contribution of mast cells to synovial inflammation in RA.

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    • "Pure imatinib was utilized for both of the in vitro B cell proliferation assays and mast cell cytokine release measurement. The induction of apoptosis by imatinib mesylate was investigated by annexin V (a marker for early apoptosis) or propidium iodide (a marker for cell death) using flow cytometry analysis as conducted by Juurikivi et al. [14] "
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    ABSTRACT: The goal of this work is to determine the role of the autoimmune cells in Rheumatoid arthritis (RA) induction and the immunomodulatory mechanism of therapy with Tyrosine Kinase Inhibitors (TKIs) in RA attenuation. B cells were isolated from naive DBA/1 mouse spleens and stimulated for 72 hours with LPS as a positive control forming a mouse model of RA in the presence or absence of 1–5 μM imatinib. B cell staging were assessed by adding 1 μCi of [3H] thymidine for measuring proliferation in the final 18 hours of the stimulation, and a Beta plate scintillation counter was used to quantitate incorporated radioactivity. Samples of C1.MC/57.1 mast cells were stimulated with 100 ng/mL of Self Cell Factor (SCF) as a positive control of a mouse model of RA in the absence or presence of 1-5 μM of imatinib. Tumour Necrotic Factor (TNF) levels in culture supernatants from C1.MC/57.1 mast cells were measured by ELISA. The histologic grade (HG) and the level of TNF of the mouse model of RA were 1/10 and 10 times respectively those in the control one. This inverse proportion clarifies that RA disease is the result of big increase in TNF level perpetuating local inflammation and joint destruction leads to a major decrease in with the same ratio. The addition of 1 and 5 μM doses of imatinib increased by 200% and 300% respectively while decreased TNF level to be 12.5% and 10% respectively of that in the mouse model of RA restoring rate of TNF level of normal tissue. This demonstrates that effective mitigation of symptoms of RA is the result of a significant increase in HG because of the cell cycle arrest resulting from the treatment of TKIs which leads to a significant reduction in the level of TNF but with a different ratio to increase HG unlike happened in incidence of RA. http://www.hrpub.org/journals/article_info.php?aid=416
    • "Reminding that, tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of RA [13] and c-Kit as a receptor tyrosine kinase is critical for mast cell development and activation. Juurikivi et al. in 2005 demonstrated that, inhibition of mast cells c-kit in human rheumatoid synovial tissue may be a new means of inhibiting mast cell activity and of abrogating the contribution of this cell in synovial inflammation in RA [39]. "
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    ABSTRACT: Imatinib mesylate is a selective protein tyrosine kinase inhibitor, which was developed to inhibit BCR/Abl, PDGF-R, c-KIT, c-fms, TCR/Abl, Lck, FLT-3 and MAPKs on various cell types. On immune system, imatinib has anti-proliferative activity and immunomodulatory effects in lymphocytes, macrophages, mast cells and dendritic cells with abrogation of multiple signal transduction pathways involving in auto immune diseases pathogenesis e.g. with inhibition of IFN-γ, TNF-α, IL-1β and IL-17 pro-inflammatory cytokines and MMPs secretion. To date the efficacy of imatinib in numerous animal model of autoimmune diseases (rheumatoid arthritis, multiple sclerosis, autoimmune diabetes and glomerulonephritis) has been demonstrated, but application of this drug in human autoimmune diseases should be tested in future clinical trials. This review provides an update on the use of tyrosine kinase inhibitor imatinib mesylate in treatment of autoimmune diseases and its related recent patents that could be developed as a novel and available therapy for the management of the autoimmunity improvement.
    Recent Patents on Inflammation & Allergy Drug Discovery 08/2013; 7(3). DOI:10.2174/1872213X113079990021
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    • "However, with the exception of MCs, expression decreases as these hematopoietic cells mature, and c-Kit is not present when these cells are fully differentiated. Simultaneously, MCs have a role in the pathogenesis of RA, and inhibition of c-Kit is reported to inhibit MC activity and also abrogate the contribution of MCs to synovial inflammation in RA [48]. Recently, it was also reported that inhibition of the kit ligand/cKit axis attenuates metastasis in the mouse model, mimicking BC relapse after radiotherapy [49]. "
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    ABSTRACT: Introduction Breast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis. Methods We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored. Results First, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis. Conclusion This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.
    Breast cancer research: BCR 04/2013; 15(2):R32. DOI:10.1186/bcr3412 · 5.49 Impact Factor
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