The effect of alendronate on cytokine production, adhesion molecule expression, and transendothelial migration of human peripheral blood mononuclear cells.
Since both osteoclasts and macrophages belong to the mononuclear phagocytic system it is conceivable that bisphosphonates not only affect bone metabolism but also inflammatory responses. The migration of mononuclear cells into perivascular tissue is a central event in inflammatory reactions. We studied the effects of the aminobisphosphonate alendronate on the transendothelial migration of human peripheral blood mononuclear cells in an in vitro model. Alendronate (at a concentration of 100 microM) significantly increased the percentage of peripheral blood mononuclear cells that migrated through endothelial cell monolayers. Similar results were obtained with another aminobisphosphonate, viz, pamidronate. An overnight treatment of the endothelial cell monolayers with alendronate did not alter the rate of peripheral blood mononuclear cells that subsequently migrated. The overnight cultivation of the peripheral blood mononuclear cells in the presence of alendronate resulted in an increased surface expression of CD54 (intercellular adhesion molecule-1, ICAM-1) in both CD14(+) and CD3(+) cells; in CD14(+) cells also the expression of CD49d (alpha4 subunit of late activation antigen-4, VLA-4) increased after alendronate treatment. Alendronate treatment of peripheral blood mononuclear cells also resulted in an increased production of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). We conclude that alendronate has a distinct effect on the transendothelial migration of human peripheral blood mononuclear cells in vitro. Alendronate may either directly or indirectly, e.g., by augmenting the production of proinflammatory cytokines, influence the expression of certain adhesion molecules and thereby facilitate transendothelial migration. These effects could be related to the transient leukopenia reported following intravenous administration of relatively high doses of aminobisphosphonates for the treatment of hypercalcemia of malignancy.
Pietschmann
P
P
Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Stohlawetz
P
P
Brosch
S
S
Steiner
G
G
Smolen
J S
JS
Peterlik
M
M
D019386:Alendronate / Q000494:pharmacology*; D015703:Antigens, CD / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D039441:Integrin alpha4; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000096:biosynthesis; D016023:Integrins / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D000077268:Pamidronate; D010641:Phenotype; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D016207:Cytokines; D004164:Diphosphonates; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D007375:Interleukin-1; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D007371:Interferon-gamma; D000077268:Pamidronate; D019386:Alendronate