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 7

Imatinib inhibits SFMC cytokine production and FLS PDGFRβ signaling.

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Imatinib inhibits SFMC cytokine production and FLS PDGFRβ signaling. (A)...
(A) Imatinib inhibits cytokine production by SFMCs derived from a human RA patient. SFMCs were stimulated with 100 ng/ml LPS in the presence of 0–8 μM imatinib, and after 48 hours culture, supernatants were analyzed for TNF-α, IL-12(p40), and IL-1α. Values are mean ± SEM. *P < 0.05 compared with stimulated cells without imatinib. Results are representative of independent experiments performed on SFMCs isolated from 2 RA patients. (B) Modulation of FLS proliferation by imatinib. FLSs from a human RA patient were incubated with 25 ng/ml PDGF-BB in the presence of 0–6 μM imatinib. After 48 hours, FLS cultures were pulsed with [3H]thymidine for 18 hours. Data represent mean cpm ± SEM of quadruplicates and are representative of experiments involving FLS lines derived from 4 RA patients. **P < 0.001 compared with stimulated cells without imatinib. (C and D) Imatinib inhibits PDGFRβ activation in FLS derived from a human RA patient. Cultured FLSs were preincubated with imatinib for 3–4 hours followed by stimulation with 25 ng/ml PDGF-BB for 10 minutes. Lysates were generated and IB analysis performed with antibodies specific for phospho-PDGFRβ and total PDGFRβ (C) and phospho-Akt and total Akt (D). IBs are representative of independent experiments performed on FLS lines derived from 4 RA patients.