Zoledronic Acid Inhibits the Function of Toll-Like Receptor 4 Ligand Activated Dendritic Cells.

Zoledronic acid (ZA; Zometa®) is a cyclic nitrogen-containing bisphosphonate with anti-tumor activity used to treat patients with malignant diseases. As a side effect, ZA induces inflammatory responses which are accompanied by expansion of gd T cells that probably mediate its anti-tumor activity. In our study we analyzed the effects of ZA on the function and differentiation of monocyte-derived dendritic cells (DC). We investigated the differentiation of immature and LPS-stimulated DCs incubated with different ZA concentrations which are usually achieved in treated patients. Expression of DC-specific marker molecules was assessed by FACS. Furthermore, the activation state and involvement of different signal transduction pathways were evaluated by Western blot. To monitor DC function we used a migration assay and analyzed the cytokine secretion. We found that DC activation with TLR4 ligand LPS is modulated by ZA. We show that the expression of the surface maturation markers CD80, CD86, CD40, CD54, CD83 and DC-SIGN is diminished with increasing ZA levels upon LPS activation. The migratory capacity of LPS stimulated DCs towards the chemokine CCL19/MIP-3beta and the secretion of the activatory cytokine IL-12 are reduced at higher ZA levels. Increasing ZA concentrations lead to the down-regulation MyD88 and diminish the nuclear localization of NF-kB family members RelB and c-Rel as well as interferon-regulatory factors IRF-3 and IRF-8 in LPS activated DCs. Hence, ZA concentrations used to treat patients have inhibitory effects on DC differentiation and activation. This might lead to immuno-suppression and negatively affect tumor rejection or result in infectious complications.