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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.
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Submitted August 29, 2005
Accepted March 3, 2006
The proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation
Alessio Nencioni, Karin Schwarzenberg, Katharina M Brauer, Susanne M Schmidt, Alberto Ballestrero, Frank Grunebach, and Peter Brossart*
Department of Internal Medicine, University of Genova, Genova, Italy
Department of Hematology, Oncology and Immunology, University of Tubingen, Tubingen, Germany
* Corresponding author; email: peter.brossart{at}med.uni-tuebingen.de.
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-labelled dextran internalization and mannose-receptor CD206 downregulation. DCs treated with bortezomib show skewed phenotypic maturation in response to stimuli of bacterial (lipopolysaccharide (LPS)) and endogenous source (including TNF- and CD40L), as well as reduced cytokine production and immunostimulatory capacity. LPS-induced CCL-2/MCP-1 and CCL5/RANTES secretion by DCs were prevented by DC treatment with bortezomib. Finally, CCR7 upregulation in DC 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 downregulate MyD88, an essential adaptor for TLR signalling, and to relieve LPS-induced activation of NF- B, IRF-3, 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 signalling and for the treatment of inflammatory and immune-mediated disorders.
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