Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of æ T cells

Bisphosphonates distributed to bone exert toxic effects specifically towards osteoclasts. On the other hand, intravenous administration of a nitrogen-containing bisphosphonate (N-BP) such as zoledronate induces acute-phase reactions (APRs), including influenza-like fever 1 day later, indicating an interaction with immunocompetent cells circulating blood. Although it has been reported that activation of gamma delta T cells is pivotal to induce an APR following treatment with zoledronate, downstream events, including the production of inflammatory cytokines after activation of gamma delta T cells, remain obscure. We investigated the effects of zoledronate on inflammatory cytokine expression in human peripheral blood mononuclear cells (PBMCs) in vitro. While zoledronate induced mRNA expressions of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, IL-6 and interferon-gamma (IFN-gamma) in PBMC, depletion of gamma delta T cells abolished that zoledronate-induced expression of those cytokines, indicating the necessity of gamma delta T cells for expression induction by zoledronate. However, which types of cells were responsible for the production of those cytokines in blood remained unclear. As it is generally accepted that monocytes and macrophages are primary sources of inflammatory cytokines, CD14(+) cells from PBMC were exposed to zoledronate in the presence of PBMC, which resulted in induced expression of mRNAs for IL-1 beta, IL-6 and IFN-gamma, but not for TNF-alpha. These results indicate that CD14(+) cells are responsible, at least in part, for the production of IL-1 beta, IL-6 and IFN-gamma in blood exposed to zoledronate. This suggests that CD14(+) cells play an essential role in the occurrence of APRs following N-BP administration.