Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis
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
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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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 4

Inhibition of macrophage c-Fms and downstream MAPK pathways by imatinib.

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Inhibition of macrophage c-Fms and downstream MAPK pathways by imatinib....
(A and B) Isolated resident peritoneal macrophages were serum starved, preincubated with imatinib, and stimulated with 100 ng/ml M-CSF for 10 minutes in the presence of imatinib and lysates generated for IB analysis. IBs were probed with antibodies specific for phospho–c-Fms and total Fms (A) or phospho–Akt (Ser473) and total Akt (B). (C) Peritoneal macrophage lysates generated using the stimulation conditions described in A and B were printed on RPP arrays. RPP arrays were probed with a variety of antibodies specific for MAPK pathway and other protein tyrosine kinases, and normalized kinase levels displayed as a heatmap.