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: Yosuke Shikama, Yasuhiro Nagai, Satoru Okada, Takefumi Oizumi, Hidetoshi Shimauchi, Shunji Sugawara, Yasuo Endo
• Journal: Toxicology letters (Toxicol Lett) Vol. 199 Issue 2 Pg. 123-8 (Nov 30 2010) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 20804833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Bone Density Conservation Agents
• Interleukin-1
• Interleukin-1beta
• Lipopolysaccharides
• Protein Precursors
• interleukin 1 precursor
• Clodronic Acid
• Caspase 1
• Alendronate

Topics

• Alendronate (pharmacology)
• Animals
• Bone Density Conservation Agents (pharmacology)
• Caspase 1 (metabolism)
• Cell Line
• Clodronic Acid (pharmacology)
• Interleukin-1 (biosynthesis)
• Interleukin-1beta (biosynthesis)
• Lipopolysaccharides (toxicity)
• Macrophages (drug effects, immunology)
• Male
• Mice
• Mice, Inbred BALB C
• Protein Precursors (biosynthesis)