Imatinib and
nilotinib are inhibitors that selectively target a set of
protein tyrosine kinases, including abelson
kinase (Abl), together with the chimeric
oncoprotein, breakpoint cluster region-abelson
kinase (Bcr-Abl), as well as
stem cell factor receptor (KIT),
platelet-derived growth factor receptor (PDGFR),
discoidin domain receptor (DDR), and colony stimulating factor-1 receptor (CSF-1R). The aim of the present study was to investigate whether
imatinib or
nilotinib was effective against
arthritis in the
glucose-6-phosphate isomerase (GPI)-induced
arthritis mouse model.
Imatinib or
nilotinib was administered orally to the arthritic mice at different time points. Efficacy was evaluated by visual scoring and by determining the production of anti-GPI antibody. Splenocytes from the arthritic mice were cultured with GPI in the presence of
imatinib or
nilotinib in vitro, and
cytokine levels in the culture supernatants were analyzed. To investigate the effects of
imatinib and
nilotinib on T-cell proliferation, lymph node cells from the arthritic mice were cultured with GPI in the presence of
imatinib or
nilotinib in vitro.
Interleukin (IL)-17
mRNA expression in the arthritic ankle joints from the onset of
arthritis was analyzed by real-time polymerase chain reaction (PCR). The administration of
imatinib from day 0 showed suppression of
arthritis (P < 0.05), the administration of
nilotinib from day 0 resulted in pronounced suppression of
arthritis (P < 0.01), and that from day 7 showed significant inhibition of the progression of
arthritis (P < 0.05). A reduction in anti-GPI
antibodies was correlated with the therapeutic efficacy of
imatinib, but not with that of
nilotinib.
Imatinib dose-dependently inhibited
tumor necrosis factor (TNF)-α,
IL-6,
interferon (IFN)-γ, and
IL-17 production by splenocytes in vitro, while
nilotinib inhibited only
IL-17 and IFN-γ production in a dose-dependent fashion.
Imatinib at 3 μM exerted a mild antiproliferative effect on CD4+ T cells (P < 0.05), whereas
imatinib at 10 μM and
nilotinib at 3 and 10 μM demonstrated a marked antiproliferative effect (P < 0.01). The IL17 gene expression level on day 7 tended to be higher than that on day 14. These findings suggest that
imatinib and
nilotinib could prevent autoimmune
arthritis, essentially via distinct mechanisms, in that
imatinib inhibits both inflammatory and T-cell-derived
cytokine production, whereas
nilotinib suppresses T-cell-derived
cytokine production.
Imatinib and
nilotinib could have therapeutic potential for
rheumatoid arthritis (RA) and other inflammatory diseases.