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-alpha 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-alpha 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / metabolism
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Arthritis, Experimental / pathology
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Autoantigens / immunology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Benzamides
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Cell Proliferation / drug effects
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Collagen Type II / immunology
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Humans
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Imatinib Mesylate
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Male
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Mast Cells / drug effects
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Mast Cells / metabolism
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Mast Cells / pathology
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Mice
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Mice, Inbred DBA
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Mice, Transgenic
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Phosphorylation / drug effects
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Piperazines / pharmacology
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Piperazines / therapeutic use*
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-kit / metabolism
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use*
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Signal Transduction / drug effects
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Stem Cell Factor / pharmacology
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Synovial Fluid / cytology
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Synovial Fluid / drug effects
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Synovial Fluid / metabolism
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Autoantigens
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Benzamides
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Collagen Type II
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Stem Cell Factor
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Tumor Necrosis Factor-alpha
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Imatinib Mesylate
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-kit
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Receptor, Macrophage Colony-Stimulating Factor
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Receptor, Platelet-Derived Growth Factor beta