Zoledronic acid inhibits the function of Toll-like receptor 4 ligand activated monocyte-derived dendritic cells.
Zoledronic acid (ZA) is a nitrogen-containing bisphosphonate with antitumor activity used to treat patients with malignant diseases. ZA treatment induces, as a side effect, inflammatory responses, which are accompanied by expansion of gammadelta T cells. In our study, we analyzed the function and differentiation of monocyte-derived immature and lipopolysaccharide (LPS)-stimulated dendritic cells (moDCs) treated with different ZA concentrations, which are achieved in patients. We found that moDC activation with TLR4 ligand LPS is modulated by ZA. The expression of maturation markers was diminished with increasing ZA levels upon LPS activation. The migratory capacity, interleukin-12 secretion and generation of cytotoxic- T-cell responses were reduced at higher ZA levels. Increasing ZA concentrations downregulated nuclear factor-kappaB family members and interferon-regulatory factor (IRF)-3. Surprisingly, in immature moDCs, low ZA concentrations caused upregulation of RelB, c-Rel, IRF-3 and IRF-8. We conclude that ZA concentrations used to treat patients have inhibitory effects on DC activation. This might lead to immunosuppression or result in infectious complications.
Bringmann
A
A
Department of Hematology, Oncology and Immunology, University of Tuebingen, Tuebingen, Germany.
Schmidt
S M
SM
Weck
M M
MM
Brauer
K M
KM
von Schwarzenberg
K
K
Werth
D
D
Grünebach
F
F
Brossart
P
P
D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000502:physiology*; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000077211:Zoledronic Acid