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Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
 
Ann Rheum Dis. Aug 2005; 64(8): 1126–1131.
PMCID: PMC1755598

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

Abstract

Background: 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.

Objective: 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.

Methods and results: Double staining with tumour necrosis factor (TNF) α and tryptase antibodies showed the presence of TNFα positive mast cells in human rheumatoid synovial tissue. Selective activation of mast cells by anti-IgE resulted in production of TNFα in synovial tissue cultures. Inhibition of the c-kit tyrosine kinase with imatinib mesylate (1.0–10 µmol/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 TNFα production in synovial tissue cultures.

Conclusion: 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.

Figure 1
 Imatinib induces apoptosis of cultured mast cells by inhibiting c-kit. (A) Human mast cell line (HMC-1) cells cultured with increasing doses of imatinib mesylate for 5 days. Imatinib was added on day 0 and trypan blue-excluding viable cells ...
Figure 2
 Imatinib induces apoptosis of non-malignant HuMC. (A) HuMC were cultured for 20–24 hours in the presence of either SCF or SCF and IL6. Thereafter, the amount of apoptotic nucleosomes was assessed with an ELISA. Data represent mean (SEM) ...
Figure 3
 TNFα positive mast cells can be seen in the synovial tissue of control explant cultures. (A) Synovial tissue stained with anti-tryptase antibody shows mast cells in synovial tissue as brown staining cells. (B) Synovial tissue stained ...
Figure 4
 The specific activation of mast cells in synovial tissue results in the production of TNFα, which is partly inhibited by imatinib. The indicated concentrations of imatinib were added to synovial tissue cultures. Mast cells were activated ...
Figure 5
 Inhibition of c-kit by imatinib induces apoptosis of mast cells in synovial tissue. Synovial tissue obtained from patients with RA was cultured in the presence of imatinib mesylate (1 µmol/l). The appearance of apoptotic cells was studied ...

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Group