The kinase inhibitor imatinib mesylate inhibits TNF-{alpha} production in vitro and prevents TNF-dependent acute hepatic inflammation.
Imatinib exerts potent antileukemic effects in vitro and in vivo. Despite its well known antitumor activity, the potential of imatinib for the treatment of inflammatory diseases remains elusive so far. Our current report provides strong evidence that imatinib has potent antiinflammatory effects. It potently inhibits LPS- and Con A-induced TNF-alpha production by human myeloid cells in vitro (peripheral blood mononuclear cells, CD14-selected monocytes, and monocyte-derived macrophages). Of note, the production of the antiinflammatory cytokine IL-10 was not significantly regulated by imatinib. In line with this observation, phosphorylation of IkappaB and subsequent DNA binding of NF-kappaB, which is critically involved in TNF-alpha, but not IL-10 expression, was reduced by imatinib. Using several murine models of acute hepatitis, we could corroborate our in vitro findings, as imatinib prevented macrophage- and TNF-alpha-dependent inflammatory damage of the liver induced by injection of either Con A or d-galactosamine/LPS by inhibition of hepatic TNF-alpha production. Of note, d-galactosamine/TNF-induced hepatitis was not affected, showing that imatinib does not directly inhibit TNF-alpha-induced hepatocellular cell death. These findings suggest a potent antiinflammatory role of imatinib by modulation of TNF-alpha production in monocytes/macrophages. This observation might be of therapeutic value for the treatment of TNF-mediated diseases.
Wolf
Anna Maria
AM
Department of Gastroenterology and Hepatology, Innsbruck Medical University, 6020 Innsbruck, Austria.
Wolf
Dominik
D
Rumpold
Holger
H
Ludwiczek
Susanne
S
Enrich
Barbara
B
Gastl
Guenther
G
Weiss
Guenter
G
Tilg
Herbert
H
D000818:Animals; D001549:Benzamides; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism*; D003208:Concanavalin A / Q000633:toxicity; D005260:Female; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000068877:Imatinib Mesylate; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D001549:Benzamides; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D016753:Interleukin-10; D000068877:Imatinib Mesylate