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Blood, 15 July 2006, Vol. 108, No. 2, pp. 551-558. Prepublished online as a Blood First Edition Paper on March 14, 2006; DOI 10.1182/blood-2005-08-3494.
IMMUNOBIOLOGY Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activationFrom the Department of Internal Medicine, University of Genoa, Italy; and the Department of Hematology, Oncology, and Immunology, University of Tübingen, Germany.
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-
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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-3
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-
B, 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. 
