title: The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA.
abstract: Plasmacytoid dendritic cells (pDCs) produce a vast amount of interferon (IFN)-α in response to nucleic acids from viruses and damaged self-cells through Toll-like receptor (TLR)7 and TLR9. Pharmaceutical agents that suppress IFN-α production by pDCs are instrumental in elucidating the mechanisms behind IFN-α production, and in developing novel therapies for inflammatory disorders that involve pDCs. Here, we show that a tyrosine kinase inhibitor for chronic myeloid leukemia with multiple targets, dasatinib, strongly suppresses production of IFN-α and proinflammatory cytokines by human pDCs stimulated with multimeric CpG oligodeoxynucleotides (CpG-A) without reducing viability. In contrast, other tyrosine kinase inhibitors, imatinib, and nilotinib, did not suppress the cytokine production at clinically relevant concentrations. Inhibitors of SRC family kinases (SFKs), which are prominent targets of dasatinib, also suppressed the cytokine production. Notably, however, dasatinib, but not SFK inhibitors, abrogated prolonged localization of CpG-A in early endosomes, which is a critical step for pDCs to produce a large amount of IFN-α. This study suggests that dasatinib suppresses IFN-α production by pDCs by inhibiting SFK-dependent pathways and SFK-independent endosomal retention of CpG DNA. Kinases controlling the distinctive endosomal trafficking in pDCs may be exploited as targets to develop novel therapies for pDC-related inflammatory disorders.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Fujita
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitawaki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sato
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
authors.forename: Shimeru
authors.initials: S
authors.lastname: Kamihira
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Kadowaki
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009838:Oligodeoxyribonucleotides / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051217:Toll-Like Receptor 9 / Q000819:agonists; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C526902:CpG ODN 2216; D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D009838:Oligodeoxyribonucleotides; C483020:ProMune; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D019061:src-Family Kinases; D000069439:Dasatinib