Rapamycin induces a caspase-independent cell death in human monocytes.
The immunosuppressive activity of rapamycin (RAPA) and its efficacy as an anti-rejection agent in organ transplantation have been ascribed principally to its anti-proliferative effects on T cells, while the activity on monocytes is partially unknown. In vitro, RAPA reduced monocyte survival by inducing a caspase-independent cell death. RAPA-induced monocyte cell death (RAPA-CD) was impeded by activation of granulocyte macrophage-colony stimulating factor family receptors or toll-like receptor 4, and by exposure to inflammatory cytokines. In vivo, in patients who received RAPA monotherapy as part of pre-conditioning for islet transplantation, RAPA affected survival of myeloid lineage cells. In the peripheral blood, CD33(+) and CD14(+) cells decreased, whereas lymphocytes appeared unaffected. In the bone marrow, myeloid precursors such as CD15(+) and CD15(+)/CD16(+) were selectively and significantly decreased, but no major cytotoxic effects were observed. The RAPA-CD suggests a dependence of monocytes on mammalian target of RAPA pathways for nutrient usage, and this feature implies that RAPA could be selectively useful as a treatment to reduce monocytes or myeloid cells in conditions where these cells negatively affect patient, suggesting a potential anti-inflammatory action of this drug.
Mercalli
A
A
Immunology of Diabetes Unit, San Raffaelle Scientific Institute, via Olgettina 60, 20132 Milan, Italy.
Sordi
V
V
Ponzoni
M
M
Maffi
P
P
De Taddeo
F
F
Gatti
G
G
Servida
P
P
Bernardi
M
M
Bellio
L
L
Bertuzzi
F
F
Secchi
A
A
Bonifacio
E
E
Piemonti
L
L