Inhibition of antigen-presenting cell function by alendronate in vitro.
Bisphosphonates are potent inhibitors of bone resorption in vivo and are emerging as important and widely used drugs for the treatment of a variety of abnormal bone resorptive processes. In the current study we investigated the in vitro effects of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate), a recently developed, extremely potent bisphosphonate, on the immune functions of human peripheral blood mononuclear cells (PBMCs). PBMC proliferation induced by lectins, alloantigens, and a nominal antigen (tetanus toxoid) was inhibited in a dose-dependent manner by alendronate. Pretreatment of monocytes, but not T cells, with the compound at concentrations ranging from 10(-4) to 10(-8) M was inhibitory, indicating that alendronate acts selectively on antigen-presenting cells (APCs). Alendronate did not affect the viability of monocytes or T cells or the expression of cell surface molecules known to play critical roles in antigen presentation. Alendronate exhibited dose-dependent inhibition of the production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by activated monocytes. The inhibitory effect of 10(-6) M alendronate on PBMC proliferation was reversed by 10 U/ml recombinant rIL-1 beta, whereas other cytokines such as IL-6, TNF-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) had no effect. Thus, alendronate acts on monocytes to inhibit their antigen-presenting/accessory cell functions through a mechanism that can be overcome by exogenous IL-1. The inhibitory effect of this agent on cytokine production may contribute to its inhibitory effect on bone resorption.
Sansoni
P
P
Clinica Medica Generale, University of Parma, Italy.
Passeri
G
G
Fagnoni
F
F
Mohagheghpour
N
N
Snelli
G
G
Brianti
V
V
Engleman
E G
EG
D019386:Alendronate; D001862:Bone Resorption / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007519:Isoantigens / Q000633:toxicity; D037102:Lectins / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D013744:Tetanus Toxin / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004164:Diphosphonates; D007375:Interleukin-1; D015850:Interleukin-6; D007519:Isoantigens; D037102:Lectins; D011994:Recombinant Proteins; D013744:Tetanus Toxin; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019386:Alendronate