IL-10 restricts dendritic cell (DC) growth at the monocyte-to-monocyte-derived DC interface by disrupting anti-apoptotic and cytoprotective autophagic molecular machinery
Publication Date
2015
Journal Title
Immunol Res
Abstract
An evolving premise is that cytoprotective autophagy responses are essential to monocyte-macrophage differentiation. Whether autophagy functions similarly during the monocyte-to-dendritic cell (DC) transition is unclear. IL-10, which induces apoptosis in maturing human DCs, has been shown to inhibit starvation-induced autophagy in murine macrophage cell lines. Based on the strict requirement that Bcl-2-mediated anti-apoptotic processes are implemented during the monocyte-to-DC transition, we hypothesized that cytoprotective autophagy responses also operate at the monocyte-DC interface and that IL-10 inhibits both anti-apoptotic and cytoprotective autophagy responses at this critical juncture. In support of our premise, we show that levels of anti-apoptotic Bcl-2 and autophagy-associated LC3 and Beclin-1 proteins are coincidentally upregulated during the monocyte-to-DC transition. Autophagy was substantiated by increased autophagosome visualization after bafilomycin treatment. Moreover, the autophagy inhibitor 3-MA restricted DC differentiation by prompting apoptosis. IL-10 implemented apoptosis that was coincidentally associated with reduced levels of Bcl-2 and widespread disruption of the autophagic flux. During peak apoptosis, IL-10 produced the death of newly committed DCs. However, cells surviving the IL-10 apoptotic schedule were highly phagocytic macrophage-like cells displaying reduced capacity to stimulate allogeneic naive T cells in a mixed leukocyte reaction, increased levels of LC3, and mature autophagosomes. Thus, IL-10's negative control of DC-driven adaptive immunity at the monocyte-DC interface includes disruption of coordinately regulated molecular networks involved in pro-survival autophagy and anti-apoptotic responses.
Volume Number
63
Issue Number
1-3
Pages
131-43
Document Type
Article
EPub Date
2015/09/24
Status
Faculty
Facility
School of Medicine
Primary Department
Molecular Medicine
PMID
DOI
10.1007/s12026-015-8700-y