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Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages
A M Woltman1, J W de Fijter, S W Kamerling
1Department of Nephrology, Leiden University Medical Center, The Netherlands.
Abstract:
Rapamycin (Rapa), a recently introduced immunosuppressive drug, seems to be effective in preventing acute allograft rejection. Although its antiproliferative effect on T lymphocytes has been investigated extensively, its effect on the initiators of the immune response, the dendritic cells (DCs), is not known. Therefore, the effect of Rapa on monocyte- (mo-DCs) and CD34(+)-derived DCs in vitro but also on other myeloid cell types, including monocytes and macrophages, was examined. The present study shows that Rapa does not affect phenotypic differentiation and CD40L-induced maturation of mo-DCs. However, Rapa dramatically reduced cell recovery (40%-50%). Relatively low concentrations of Rapa (10(-9) M) induced apoptosis in both mo-DCs and CD34(+)-derived DCs, as visualized by phosphatidylserine exposure, nuclear condensation and fragmentation, and DNA degradation. In contrast, Rapa did not affect freshly isolated monocytes, macrophages, or myeloid cell lines. The sensitivity to Rapa-induced apoptosis was acquired from day 2 onward of mo-DC differentiation. Rapa exerts its apoptotic effect via a reversible binding to the cytosolic receptor protein FKBP-12, as demonstrated in competition experiments with FK506, which is structurally related to Rapa. Partial inhibition of Rapa-induced apoptosis was obtained by addition of ZVAD-fmk, which implies caspase-dependent and caspase-independent processes. The fact that Rapa exerts a specific effect on DCs but not on monocytes and macrophages might contribute to the unique actions of Rapa in the prevention of allograft rejection and other immune responses.
Insights
Rapamycin (Rapa) induces apoptosis in dendritic cells (DCs) but not monocytes or macrophages. This specific effect on DCs may explain Rapa's efficacy in preventing allograft rejection and other immune responses.
Area of Science:
- Immunology
- Pharmacology
Background:
- Rapamycin (Rapa) is an immunosuppressive drug used to prevent allograft rejection.
- Its antiproliferative effects on T lymphocytes are well-documented.
- The impact of Rapa on dendritic cells (DCs), key initiators of immune responses, remains largely unknown.
Purpose of the Study:
- To investigate the effect of Rapamycin (Rapa) on dendritic cells (DCs) derived from monocytes (mo-DCs) and CD34+ progenitor cells.
- To examine Rapa's impact on other myeloid cells, including monocytes and macrophages.
- To elucidate the mechanism of Rapa-induced apoptosis in DCs.
Main Methods:
- In vitro differentiation of mo-DCs and CD34+-derived DCs.
- Assessment of DC differentiation, maturation, and apoptosis.
- Analysis of Rapa's effect on monocytes, macrophages, and myeloid cell lines.
- Competition experiments with FK506 and addition of ZVAD-fmk to study apoptotic pathways.
Main Results:
- Rapa did not affect mo-DC phenotypic differentiation or CD40L-induced maturation.
- Rapa significantly reduced cell recovery (40%-50%) and induced apoptosis in mo-DCs and CD34+-derived DCs at low concentrations (10(-9) M).
- Sensitivity to Rapa-induced apoptosis developed in mo-DCs after 2 days of differentiation; Rapa did not affect monocytes, macrophages, or myeloid cell lines.
Conclusions:
- Rapamycin (Rapa) specifically induces apoptosis in dendritic cells (DCs) without affecting monocytes or macrophages.
- Rapa-induced apoptosis in DCs involves both caspase-dependent and -independent pathways.
- The selective effect of Rapa on DCs may underlie its unique immunosuppressive properties in allograft rejection and other immune conditions.
