Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide-induced production of interleukin-1 and tumour necrosis factor alpha in mice.
1. Aminobisphosphonates (aminoBPs), potent inhibitors of bone resorption, have been reported to induce inflammatory reactions such as fever and an increase in acute phase proteins in human patients, and to induce the histamine-forming enzyme, histidine decarboxylase, in mice. In the present study, we examined the effect of aminoBP, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (AHBuBP), on the production of the pro-inflammatory cytokines, IL-1 and TNFalpha, in mice. 2. Intraperitoneal injection of AHBuBP did not itself produce detectable levels of IL-1 (alpha and beta) and TNFalpha in the serum. However, the elevation of serum IL-1 induced by lipopolysaccharide (LPS) was greatly augmented in mice injected with AHBuBP 3 days before the LPS injection, whereas the LPS-induced elevation of serum TNFalpha was almost completely abolished. 3. Spleen and bone marrow cells taken from mice injected with AHBuBP produced IL-1beta in vitro spontaneously, and the production was augmented following the addition of LPS. Cells that accumulated in the peritoneal cavity in response to AHBuBP produced a particularly large amount of IL-1beta. However, AHBuBP treatment of mice did not lead to an impairment of the in vitro production of TNFalpha by these three types of cells. 4. Liposomes encapsulating dichloromethylene bisphosphonate (a non-amino BP) selectively deplete phagocytic macrophages. When an intraperitoneal injection of these liposomes was given 2 days after an injection of AHBuBP, there was a marked decrease in the LPS-induced elevation of serum IL-1 (alpha and beta) (LPS being injected 3 days after the injection of AHBuBP). 5. These results indicate that AHBuBP has contrasting effects on the in vivo LPS-induced production of IL-1 and TNFalpha in mice, enhancing the production of IL-1 by phagocytic macrophages and suppressing the production of TNFalpha, although underling mechanisms remain to be clarified.
Sugawara
S
S
Department of Microbiology & Immunology, School of Dentistry, Tohoku University, Sendai, Japan.
Shibazaki
M
M
Takada
H
H
Kosugi
H
H
Endo
Y
Y
D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D019386:Alendronate