The Kinase Inhibitor Imatinib Mesylate Potently Inhibits TNF-α Production by Myeloid Cells and Prevents T-Cell-Mediated Hepatic Injury in Mice.

Abstract Imanitib mesylate (Gleevec®) exhibits potent anti-leukemic effects in vitro and in vivo. Despite of it`s well known anti-leukemic effects, the potential of Imatinib in the treatment of inflammation remains elusive so far. Our current report provides strong evidence that Imatinib indeed exerts anti-inflammatory effects. It potently inhibits LPS- and ConA-induced TNF-α and IFN-γ production of human myeloid cells in vitro (PBMNC, CD14-selected monocytes and monocyte-derived macrophages). Of note, the production of the anti-inflammatory cytokine IL-10 was only slightly affected by Imatinib. In line with this observation, the activation of NF-κB, which has recently been shown to be critically involved in TNF-α but not IL-10 expression, was significantly impaired by Imatinib. In addition, Imatinib reduced either LPS or ConA-induced intracellular phophotyrosine content. For in vivo testing of the anti-inflammatory role of Imatinib in a murine model of inflammation, we injected BALB/c mice with either 75 mg/kg body weight Imatinib or solvent before administration of ConA. The latter has recently been shown to induce T-cell, macrophage and TNF-α-dependent inflammatory damage of the liver. Imatinib pre-treatment prevented the development of acute hepatic injury, which was paralleled by reduced intrahepatic TNF-α mRNA and circulating TNF-α protein levels. Improvement of liver pathology by Imatinib was further assessed by light microscopy and TUNEL staining. Of note, Imatinib protected mice also from GalN/LPS- but not from GalN/TNF-induced liver pathology, which corroborates our in vitro findings that Imatinib potently inhibits TNF-α production of myeloid cells. These findings point out to a potent anti-inflammatory role of the tyrosine kinase inhibitor Imatinib, which might be of therapeutic benefit for the treatment of TNF-α-mediated immune-pathologies, such as inflammatory bowel disease (IBD), aGvHD or immune-mediated liver injury.