title: Pro-IL-1β accumulation in macrophages by alendronate and its prevention by clodronate.
abstract: Nitrogen-containing bisphosphonates (NBPs), anti-bone-resorptive drugs, exhibit inflammatory side effects (fever, jaw osteomyelitis or osteonecrosis, etc.). We previously reported that in mice: (i) a single intraperitoneal injection of alendronate (an NBP, 40 μmol/kg or less) induces various inflammatory reactions, (ii) these effects, which are minimal in IL-1-deficient mice, can be prevented by co-administration of clodronate (a non-NBP, 40 μmol/kg or less), and (iii) alendronate increases IL-1β in tissues (liver, spleen, and lung), but strangely not in blood. Here, we found the following in mice. (a) The IL-1β in tissues is pro-IL-1β. (b) Unlike LPS, alendronate induces minimal activation of caspase-1 (pro-IL-1β-processing enzyme). (c) The tissue pro-IL-1β elevations are largely absent in macrophage-depleted mice. (d) In vitro, 100 μM alendronate directly stimulates RAW 264 cells (murine macrophage-like cells) to produce pro-IL-1β, and 1 μM clodronate inhibits this effect. These results suggest that in mice: (i) the major pro-IL-1β-producing cells in response to alendronate are macrophages, (ii) alendronate directly stimulates them to produce pro-IL-1β, but the release of mature IL-1β is below detectable levels due to insufficient activation of caspase-1, and (iii) clodronate inhibits the pro-IL-1β production by acting directly on macrophages, although the in vivo mechanism may differ from the in vitro one.
authors.affiliation: Division of Molecular Regulation, Graduate School of Dentistry, Tohoku University, Aoba-ku, Sendai, Japan. shikama-thk@umin.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shikama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nagai
authors.forename: Satoru
authors.initials: S
authors.lastname: Okada
authors.forename: Takefumi
authors.initials: T
authors.lastname: Oizumi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Shimauchi
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D004002:Clodronic Acid / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011498:Protein Precursors / Q000096:biosynthesis*
chemical_list: D050071:Bone Density Conservation Agents; D007375:Interleukin-1; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011498:Protein Precursors; C043830:interleukin 1 precursor; D004002:Clodronic Acid; D020170:Caspase 1; D019386:Alendronate