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Generation of Human Monocyte-derived Dendritic Cells from Whole Blood
Published on: December 24, 2016
Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells
Alessio Nencioni1, Anna Garuti, Karin Schwarzenberg
1Department of Internal Medicine, University of Genova, Genova, Italy. A.Nencioni@gmx.net
Abstract:
Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level.
Insights
Proteasome inhibitors induce apoptosis in dendritic cells (DC), key immune cells. This finding reveals a new way these cancer drugs impact the immune system at the antigen-presenting cell level.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Proteasome inhibitors show significant antitumor effects in various cancers.
- The impact of proteasome inhibitors on the immune system, particularly dendritic cells (DCs), remains incompletely understood.
- Dendritic cells are crucial antigen-presenting cells initiating immune responses.
Purpose of the Study:
- To investigate the effects of proteasome inhibitors on dendritic cells (DCs).
- To elucidate the mechanisms underlying DC apoptosis induced by proteasome inhibitors.
- To determine if active protein synthesis is required for this apoptotic response.
Main Methods:
- Human monocyte-derived DCs were exposed to proteasome inhibitors (bortezomib, MG132, epoxomicin).
- Apoptosis, mitochondrial disruption, caspase activation, and Bax protein expression were analyzed.
- The effect of cycloheximide (translation inhibitor) on proteasome inhibitor-induced apoptosis was assessed.
Main Results:
- Proteasome inhibitors induced apoptosis in human monocyte-derived DCs.
- Reduced viable DC yield was observed when inhibitors were present during monocyte differentiation.
- Apoptosis involved mitochondrial disruption, caspase activation, and Bax redistribution, activating the intrinsic pathway.
- Active protein synthesis was essential for the observed DC apoptosis.
Conclusions:
- Proteasome inhibitors induce apoptosis in dendritic cells.
- This apoptosis is mediated by mitochondrial disruption and the intrinsic apoptotic pathway.
- Induction of DC apoptosis represents a novel mechanism by which proteasome inhibitors modulate immune responses at the antigen-presenting cell level.
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