title: 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-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.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Paniagua
authors.forename: Orr
authors.initials: O
authors.lastname: Sharpe
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.forename: Steven M
authors.initials: SM
authors.lastname: Chan
authors.forename: Anna
authors.initials: A
authors.lastname: Chang
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Beren H
authors.initials: BH
authors.lastname: Tomooka
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Thomas
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Song
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D024043:Collagen Type II / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000494:pharmacology; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001324:Autoantigens; D001549:Benzamides; D024043:Collagen Type II; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020797:Receptor, Platelet-Derived Growth Factor beta