Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis.
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.
Paniagua
Ricardo T
RT
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Sharpe
Orr
O
Ho
Peggy P
PP
Chan
Steven M
SM
Chang
Anna
A
Higgins
John P
JP
Tomooka
Beren H
BH
Thomas
Fiona M
FM
Song
Jason J
JJ
Goodman
Stuart B
SB
Lee
David M
DM
Genovese
Mark C
MC
Utz
Paul J
PJ
Steinman
Lawrence
L
Robinson
William H
WH
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
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