title: Effects of imatinib on monocyte-derived dendritic cells are mediated by inhibition of nuclear factor-kappaB and Akt signaling pathways.
abstract: Dendritic cells are the most powerful antigen-presenting cells playing a decisive role for the initiation and maintenance of primary immune responses. However, signaling pathways involved in the differentiation of these cells have not been fully determined. Imatinib is a novel tyrosine kinase inhibitor effective against Abl kinases, c-Kit, and platelet-derived growth factor receptor. Using this compound, we show that human monocyte-derived dendritic cells generated in the presence of therapeutic concentrations of imatinib show a reduced expression of CD1a, MHC class I and II, and costimulatory molecules as well as decreased secretion of chemokines and cytokines resulting in an impaired capacity of dendritic cells to elicit primary T-cell responses. Using Western blot analyses, we found that these effects are mediated by inhibition of phosphatidylinositol 3-kinase/Akt pathways and a pronounced down-regulation of nuclear localized protein levels of nuclear factor-kappaB family members. Importantly, using blocking antibodies and tyrosine kinase inhibitors, we show that the inhibitory effects of imatinib on dendritic cell differentiation are not mediated via platelet-derived growth factor receptor and c-Kit. Taken together, our study reveals that imatinib inhibits dendritic cell differentiation and function via Akt and nuclear factor-kappaB signal transduction. Importantly, we show that imatinib can inhibit the function of normal, nonmalignant cells that may result in immunosuppression of these patients.
authors.affiliation: Department of Hematology, Oncology, and Immunology, University of Tübingen, Otfried-Muller Strasse 10, D-72076 Tübingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Appel
authors.forename: Anette
authors.initials: A
authors.lastname: Rupf
authors.forename: Markus M
authors.initials: MM
authors.lastname: Weck
authors.forename: Oliver
authors.initials: O
authors.lastname: Schoor
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.forename: Toni
authors.initials: T
authors.lastname: Weinschenk
authors.forename: Frank
authors.initials: F
authors.lastname: Grünebach
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D007165:Immunosuppression Therapy; D018950:Lipopolysaccharide Receptors; D009000:Monocytes; D016328:NF-kappa B / Q000096:biosynthesis / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt