Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis
Ricardo T. Paniagua, … , Lawrence Steinman, William H. Robinson
Ricardo T. Paniagua, … , Lawrence Steinman, William H. Robinson
Published October 2, 2006
Citation Information: J Clin Invest. 2006;116(10):2633-2642. https://doi.org/10.1172/JCI28546.
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Research Article Autoimmunity

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

Abstract

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit–expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-α release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-α production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

Authors

Ricardo T. Paniagua, Orr Sharpe, Peggy P. Ho, Steven M. Chan, Anna Chang, John P. Higgins, Beren H. Tomooka, Fiona M. Thomas, Jason J. Song, Stuart B. Goodman, David M. Lee, Mark C. Genovese, Paul J. Utz, Lawrence Steinman, William H. Robinson

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Figure 3

Imatinib inhibits mast cell c-Kit activation and proinflammatory cytokine production.

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Imatinib inhibits mast cell c-Kit activation and proinflammatory cytokin...
(A) C1.MC/57.1 mast cells were stimulated with 100 ng/ml SCF in the presence of 0–5 μM imatinib, and after 48 hours culture supernatants were collected and analyzed for TNF-α, GM-CSF, and IL-6 by a bead-based cytokine assay. Values are mean ± SEM. *P < 0.05, **P < 0.01 compared with stimulated cells without imatinib. (B and C) C1.MC/57.1 mast cells were serum starved, preincubated with imatinib, and stimulated with 100 ng/ml SCF for 10 minutes in the presence or absence of imatinib, and lysates were generated for IB analysis. IBs were probed with antibodies specific for phospho–c-Kit and total c-Kit (B) and phospho-Akt (Ser473) and total Akt (C). (D) Mast cell lysates generated using the stimulation conditions described in B and C were printed to generate RPP arrays. RPP arrays were probed with a variety of antibodies specific for phosphorylated (activated) protein tyrosine kinases and levels normalized to levels in unstimulated cells. Yellow represents anti-protein tyrosine kinase antibody reactivity, and blue represents lack of reactivity. (E) Mast cells are present in CIA synovium. A representative joint section from a mouse with CIA was stained with toluidine blue. Mast cells present in the densely inflamed CIA synovial tissue are indicated by arrows. B, bone; JS, joint space. Original magnification, ×200.