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Ann Rheum Dis. 2005 Aug; 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


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.

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Selected References

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  • Woolley David E. The mast cell in inflammatory arthritis. N Engl J Med. 2003 Apr 24;348(17):1709–1711. [PubMed]
  • Gotis-Graham I, McNeil HP. Mast cell responses in rheumatoid synovium. Association of the MCTC subset with matrix turnover and clinical progression. Arthritis Rheum. 1997 Mar;40(3):479–489. [PubMed]
  • Lee David M, Friend Daniel S, Gurish Michael F, Benoist Christophe, Mathis Diane, Brenner Michael B. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science. 2002 Sep 6;297(5587):1689–1692. [PubMed]
  • Tetlow LC, Woolley DE. Mast cells, cytokines, and metalloproteinases at the rheumatoid lesion: dual immunolocalisation studies. Ann Rheum Dis. 1995 Nov;54(11):896–903. [PMC free article] [PubMed]
  • Valent P. The riddle of the mast cell: kit(CD117)-ligand as the missing link? Immunol Today. 1994 Mar;15(3):111–114. [PubMed]
  • Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987 Nov;6(11):3341–3351. [PMC free article] [PubMed]
  • Besmer P, Murphy JE, George PC, Qiu FH, Bergold PJ, Lederman L, Snyder HW, Jr, Brodeur D, Zuckerman EE, Hardy WD. A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature. 1986 Apr 3;320(6061):415–421. [PubMed]
  • Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak MZ, Gewirtz AM, et al. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):459–463. [PMC free article] [PubMed]
  • Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A. Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res. 1992 Nov 15;52(22):6139–6143. [PubMed]
  • Turner AM, Zsebo KM, Martin F, Jacobsen FW, Bennett LG, Broudy VC. Nonhematopoietic tumor cell lines express stem cell factor and display c-kit receptors. Blood. 1992 Jul 15;80(2):374–381. [PubMed]
  • Buchdunger E, Zimmermann J, Mett H, Meyer T, Müller M, Druker BJ, Lydon NB. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996 Jan 1;56(1):100–104. [PubMed]
  • Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996 May;2(5):561–566. [PubMed]
  • Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001 Apr 5;344(14):1052–1056. [PubMed]
  • Eklund Kari K, Joensuu Heikki. Treatment of rheumatoid arthritis with imatinib mesylate: clinical improvement in three refractory cases. Ann Med. 2003;35(5):362–367. [PubMed]
  • Miyachi K, Ihara A, Hankins RW, Murai R, Maehiro S, Miyashita H. Efficacy of imatinib mesylate (STI571) treatment for a patient with rheumatoid arthritis developing chronic myelogenous leukemia. Clin Rheumatol. 2003 Oct;22(4-5):329–332. [PubMed]
  • Butterfield JH, Weiler D, Dewald G, Gleich GJ. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res. 1988;12(4):345–355. [PubMed]
  • Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugahara H, Butterfield JH, Ashman LK, Kanayama Y, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993 Oct;92(4):1736–1744. [PMC free article] [PubMed]
  • Eklund KK, Ghildyal N, Austen KF, Friend DS, Schiller V, Stevens RL. Mouse bone marrow-derived mast cells (mBMMC) obtained in vitro from mice that are mast cell-deficient in vivo express the same panel of granule proteases as mBMMC and serosal mast cells from their normal littermates. J Exp Med. 1994 Jul 1;180(1):67–73. [PMC free article] [PubMed]
  • Saito H, Ebisawa M, Sakaguchi N, Onda T, Iikura Y, Yanagida M, Uzumaki H, Nakahata T. Characterization of cord-blood-derived human mast cells cultured in the presence of Steel factor and interleukin-6. Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):63–65. [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • Mekori YA, Oh CK, Metcalfe DD. The role of c-Kit and its ligand, stem cell factor, in mast cell apoptosis. Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):136–138. [PubMed]
  • Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163–196. [PubMed]
  • Kiener HP, Baghestanian M, Dominkus M, Walchshofer S, Ghannadan M, Willheim M, Sillaber C, Graninger WB, Smolen JS, Valent P. Expression of the C5a receptor (CD88) on synovial mast cells in patients with rheumatoid arthritis. Arthritis Rheum. 1998 Feb;41(2):233–245. [PubMed]
  • Tetlow LC, Woolley DE. Distribution, activation and tryptase/chymase phenotype of mast cells in the rheumatoid lesion. Ann Rheum Dis. 1995 Jul;54(7):549–555. [PMC free article] [PubMed]
  • Akin Cem, Brockow Knut, D'Ambrosio Claudio, Kirshenbaum Arnold S, Ma Yongsheng, Longley B Jack, Metcalfe Dean D. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol. 2003 Aug;31(8):686–692. [PubMed]
  • Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001 Apr 5;344(14):1031–1037. [PubMed]
  • Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000 Aug 1;96(3):925–932. [PubMed]
  • Zermati Yael, De Sepulveda Paulo, Féger Frederic, Létard Sebastion, Kersual Joelle, Castéran Nathalie, Gorochov Guy, Dy Michel, Ribadeau Dumas Antoni, Dorgham Karim, et al. Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene. 2003 Feb 6;22(5):660–664. [PubMed]
  • Takeuchi Kouichi, Koike Kenichi, Kamijo Takehiko, Ishida Shuichi, Nakazawa Yozo, Kurokawa Yumi, Sakashita Kazuo, Kinoshita Tatsuya, Matsuzawa Shigeyuki, Shiohara Masaaki, et al. STI571 inhibits growth and adhesion of human mast cells in culture. J Leukoc Biol. 2003 Dec;74(6):1026–1034. [PubMed]
  • Ceponis A, Konttinen YT, Takagi M, Xu JW, Sorsa T, Matucci-Cerinic M, Santavirta S, Bankl HC, Valent P. Expression of stem cell factor (SCF) and SCF receptor (c-kit) in synovial membrane in arthritis: correlation with synovial mast cell hyperplasia and inflammation. J Rheumatol. 1998 Dec;25(12):2304–2314. [PubMed]

Figures and Tables

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 ...

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