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