Mutual augmentation of the induction of the histamine-forming enzyme, histidine decarboxylase, between alendronate and immuno-stimulants (IL-1, TNF, and LPS), and its prevention by clodronate

Xue Deng, Zhiqian Yu, Hiromi Funayama, Noriaki Shoji, Takashi Sasano, Yoichiro Iwakura, Shunji Sugawara, Yasuo Endo

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Nitrogen-containing bisphosphonates (N-BPs), powerful anti-bone-resorptive drugs, have inflammatory side effects, while histamine is not only an inflammatory mediator, but also an immuno-modifier. In murine models, a single intraperitoneal injection of an N-BP induces various inflammatory reactions, including the induction of the histamine-forming enzyme histidine decarboxylase (HDC) in tissues important in immune responses (such as liver, lungs, spleen, and bone marrow). Lipopolysaccharide (LPS) and the proinflammatory cytokines IL-1 and TNF are also capable of inducing HDC. We reported previously that in mice, (i) the inflammatory actions of N-BPs depend on IL-1, (ii) N-BP pretreatment augments both LPS-stimulated IL-1 production and HDC induction, and (iii) the co-administration of clodronate (a non-N-BP) with an N-BP inhibits the latter's inflammatory actions (including HDC induction). Here, we add the new findings that (a) pretreatment with alendronate (a typical N-BP) augments both IL-1- and TNF-induced HDC elevations, (b) LPS pretreatment augments the alendronate-induced HDC elevation, (c) co-administration of clodronate with alendronate abolishes these augmentations, (d) alendronate does not induce HDC in IL-1-deficient mice even if they are pretreated with LPS, and (e) alendronate increases IL-1β in all tissues tested, but not in the serum. These results suggest that (1) there are mutual augmentations between alendronate and immuno-stimulants (IL-1, TNF, and LPS) in HDC induction, (2) tissue IL-1β is important in alendronate-stimulated HDC induction, and (3) combination use of clodronate may have the potential to reduce the inflammatory effects of alendronate (we previously found that clodronate, conveniently, does not inhibit the anti-bone-resorptive activity of alendronate).

Original languageEnglish
Pages (from-to)64-73
Number of pages10
JournalToxicology and Applied Pharmacology
Volume213
Issue number1
DOIs
Publication statusPublished - 2006 May 15

Keywords

  • Alendronate
  • Bisphosphonates
  • Clodronate
  • Histidine decarboxylase
  • Interleukin-1 (IL-1)
  • Lipopolysaccharide (LPS)

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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