Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation

Alessio Nencioni, Karin Schwarzenberg, Katharina M. Brauer, Susanne M. Schmidt, Alberto Ballestrero, Frank Grünebach, Peter Brossart

Research output: Contribution to journalArticle

Abstract

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-α 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-3β 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-κB, 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.

Original languageEnglish
Pages (from-to)551-558
Number of pages8
JournalBlood
Volume108
Issue number2
DOIs
Publication statusPublished - Jul 15 2006

ASJC Scopus subject areas

  • Hematology

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    Nencioni, A., Schwarzenberg, K., Brauer, K. M., Schmidt, S. M., Ballestrero, A., Grünebach, F., & Brossart, P. (2006). Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood, 108(2), 551-558. https://doi.org/10.1182/blood-2005-08-3494