Dexamethasone counteracts the anti-osteoclastic, but not the anti-leukemic, activity of TNF-related apoptosis inducing ligand (TRAIL).
We have analyzed the effect of the synthetic glucocorticoid dexamethasone, used alone or in combination with recombinant TRAIL, on in vitro osteoclastic differentiation of peripheral blood-derived macrophages cultured in the presence of macrophage-colony stimulating factor (M-CSF) + RANKL for 12-14 days. Dexamethasone exhibited different effects based on the concentration used. Indeed, while at 10(-7) M dexamethasone reduced the number of mature osteoclasts, at 10(-8) M showed no significant effects and at 10(-9) M significantly increased the number of mature osteoclasts, with respect to cells cultured with only M-CSF + RANKL. On the other hand, the addition in culture of recombinant TRAIL inhibited the output of mature osteoclasts induced by M-CSF + RANKL. However, the presence of dexamethasone (10(-8) or 10(-9) M) into the culture medium significantly counteracted the anti-osteoclastic activity of TRAIL. In order to ascertain whether dexamethasone, might also interfere with the anti-leukemic activity of TRAIL, the degree of apoptosis induced by TRAIL was evaluated in several myeloid (OCI, MOLM, HL-60) and lymphoid (SKW6.4, MAVER, BJAB) leukemic cell lines. The levels of TRAIL-triggered apoptosis were not significantly different between leukemic cells cultured in the absence or presence of dexamethasone. Concerning the molecular mechanism mediating the dexamethasone-suppression of the TRAIL activity in pre-osteoclasts, but not in leukemic cells, we found that dexamethasone induced a significant down-regulation of the surface levels of TRAIL-R2 in cells of the osteoclastic lineage but not in leukemic cells. The ability of dexamethasone to counteract the TRAIL pathway envisions a novel mechanism mediating the pro-osteoclastic activity of dexamethasone in vivo.
Zauli
Giorgio
G
Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy.
Rimondi
Erika
E
Celeghini
Claudio
C
Milani
Daniela
D
Secchiero
Paola
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D005938:Glucocorticoids; D053245:RANK Ligand; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor