Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation.
Evidence from the animal model suggests that proteasome inhibitors may have immunosuppressive properties; however, their effects on the human immune system remain poorly investigated. Here, we show that bortezomib, a proteasome inhibitor with anticancer activity, impairs several immune properties of human monocyte-derived dendritic cells (DCs). Namely, exposure of DCs to bortezomib reduces their phagocytic capacity, as shown by FITC-labeled dextran internalization and mannose-receptor CD206 down-regulation. DCs treated with bortezomib show skewed phenotypic maturation in response to stimuli of bacterial (lipopolysaccharide [LPS]) and endogenous sources (including TNF-alpha and CD40L), as well as reduced cytokine production and immunostimulatory capacity. LPS-induced CCL-2/MCP-1 and CCL5/RANTES secretions by DCs were prevented by DC treatment with bortezomib. Finally, CCR7 up-regulation in DCs exposed to LPS as well as migration toward CCL19/MIP-3beta were strongly impaired. As a suitable mechanism for these effects, bortezomib was found to down-regulate MyD88, an essential adaptor for TLR signaling, and to relieve LPS-induced activation of NF-kappaB, IRF-3, and IRF-8 and of the MAP kinase pathway. In summary, inhibition of DC function may represent a novel mechanism by which proteasome inhibitors exert immunomodulatory effects. These compounds could prove useful for tuning TLR signaling and for the treatment of inflammatory and immune-mediated disorders.
Department of Internal Medicine, University of Genoa, Italy.
Alessio
A
Nencioni
Karin
K
Schwarzenberg
Katharina M
KM
Brauer
Susanne M
SM
Schmidt
Alberto
A
Ballestrero
Frank
F
Grünebach
Peter
P
Brossart
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88; D010587:Phagocytosis / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D001897:Boronic Acids; D016207:Cytokines; D007155:Immunologic Factors; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000069286:Bortezomib