title: Cutting edge: nitrogen bisphosphonate-induced inflammation is dependent upon mast cells and IL-1.
abstract: Nitrogen-containing bisphosphonates (NBPs) are taken by millions for bone disorders but may cause serious inflammatory reactions. In this study, we used a murine peritonitis model to characterize the inflammatory mechanisms of these agents. At dosages comparable to those used in humans, injection of NBPs into the peritoneum caused recruitment of neutrophils, followed by an influx of monocytes. These cellular changes corresponded to an initial increase in IL-1α, which preceded a rise in multiple other proinflammatory cytokines. IL-1R, IL-1α, and IL-1β were required for neutrophil recruitment, whereas other MyD88-dependent signaling pathways were needed for the monocyte influx. Mice deficient in mast cells, but not mice lacking lymphocytes, were resistant to NBP-induced inflammation, and reconstitution of these mice with mast cells restored sensitivity to NBPs. These results document the critical role of mast cells and IL-1 in NBP-mediated inflammatory reactions.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Norton
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Brian
authors.initials: B
authors.lastname: Crain
authors.forename: John S
authors.initials: JS
authors.lastname: Cho
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Miller
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
mesh_terms: D019386:Alendronate / Q000633:toxicity*; D000818:Animals; D002633:Chemotaxis / Q000502:physiology; D004002:Clodronic Acid / Q000633:toxicity; D004164:Diphosphonates / Q000633:toxicity*; D007093:Imidazoles / Q000633:toxicity*; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009504:Neutrophils / Q000276:immunology; D000077268:Pamidronate; D010538:Peritonitis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D004002:Clodronic Acid; D000077211:Zoledronic Acid; D000077268:Pamidronate; D019386:Alendronate