Alendronate attenuates eosinophilic airway inflammation associated with suppression of Th2 cytokines, Th17 cytokines, and eotaxin-2.
Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN's immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma.
Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Oh
O
Sasaki
Mitsuru
M
Imamura
Yusuke
Y
Yamazumi
Hiroaki
H
Harada
Taku
T
Matsumoto
Katsuhide
K
Okunishi
Kazuyuki
K
Nakagome
Ryoichi
R
Tanaka
Tetsu
T
Akiyama
Kazuhiko
K
Yamamoto
Makoto
M
Dohi
D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D054423:Chemokine CCL24 / Q000096:biosynthesis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D050071:Bone Density Conservation Agents; D054423:Chemokine CCL24; D016207:Cytokines; D019386:Alendronate