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Published on: October 28, 2019
Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased
Andrea M Woltman1, Sandra W van der Kooij, Paul J Coffer
1Department of Nephrology, Leiden University Medical Center, The Netherlands. a.m.woltman@lumc.nl
Abstract:
The longevity of dendritic cells (DCs) is a critical regulatory factor influencing the outcome of immune responses. Recently, we demonstrated that the immunosuppressive drug rapamycin (Rapa) specifically induces apoptosis in DCs but not in other myeloid cell types. The present study unraveled the mechanism used by Rapa to induce apoptosis in human monocyte-derived DCs. Our data demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF) preserves DC survival specifically via the phosphatidylinositol-3 lipid kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathway, which is abrogated by Rapa at the level of mTOR. Disruption of this GM-CSF signaling pathway induced loss of mitochondrial membrane potential, phosphatidyl-serine exposure, and nuclear changes. Apoptosis of these nonproliferating DCs was preceded by an up-regulation of the cell cycle inhibitor p27(KIP1). Overexpression of p27(KIP1) in DCs using adenoviral gene transduction revealed that apoptosis is directly regulated by p27(KIP1). Furthermore, both overexpression of p27(KIP1) and disruption of the GM-CSF/PI3K/mTOR signaling pathway decreased the expression of the antiapoptotic protein mcl-1. This mTOR/p27(KIP1)/mcl-1 survival seems unique for DCs and may provide novel opportunities to influence immune responses by specific interference with the life span of these cells.
Insights
Rapamycin induces apoptosis in dendritic cells (DCs) by blocking survival signals. This immune response mechanism involves the mTOR pathway and p27(KIP1), offering new ways to control immune cell lifespan.
Area of Science:
- Immunology
- Cell Biology
Background:
- Dendritic cell (DC) longevity is crucial for regulating immune responses.
- Rapamycin (Rapa) selectively induces apoptosis in DCs, unlike other myeloid cells.
Purpose of the Study:
- To elucidate the mechanism by which Rapa induces apoptosis in human monocyte-derived DCs.
- To identify the specific signaling pathways and molecules involved in Rapa-induced DC apoptosis.
Main Methods:
- Investigated the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in DC survival.
- Analyzed the phosphatidylinositol-3 lipid kinase/mammalian target of rapamycin (PI3K/mTOR) pathway.
- Utilized adenoviral gene transduction to overexpress p27(KIP1) in DCs.
- Assessed apoptosis markers including mitochondrial membrane potential and phosphatidyl-serine exposure.
- Quantified the expression of the antiapoptotic protein mcl-1.
Main Results:
- GM-CSF preserves DC survival via the PI3K/mTOR pathway, which Rapa inhibits at mTOR.
- Disruption of GM-CSF signaling triggers apoptosis, characterized by mitochondrial dysfunction and nuclear changes.
- Apoptosis in nonproliferating DCs is preceded by p27(KIP1) upregulation.
- p27(KIP1) directly regulates DC apoptosis.
- Both p27(KIP1) overexpression and GM-CSF/PI3K/mTOR pathway disruption reduce mcl-1 expression.
Conclusions:
- The mTOR/p27(KIP1)/mcl-1 pathway is critical for DC survival and appears unique to these cells.
- Targeting this pathway offers novel strategies for modulating immune responses by controlling DC lifespan.
