Mature dendritic cells are protected from Fas/CD95-mediated apoptosis by upregulation of Bcl-X L

Abstract

The clinical use of dendritic cells (DC) as tumor vaccines is very much dependent on their survival potential. Members of the tumor necrosis factor (TNF) receptor superfamily and their ligands are involved in the regulation of cell death. Fas (CD95) is a representative protein that promotes apoptosis. The Bcl-2 family of proteins functions as an integrator of diverse pro- and anti-apoptotic signals. It has been found that DC maturation facilitates their survival, and thus has an anti-apoptotic function. However, little is known about the underlying mechanisms. We investigated the effects of TNF-alpha and lipopolysaccharide (LPS) on the expression of apoptotic molecules during differentiation and maturation of DC under serum-free conditions, and correlated this to the sensitivity to apoptosis by the Fas-mediated pathway. Indeed, DC activation effectively inhibited DC apoptosis, which was predominantly accompanied by the upregulation of Bcl-X(L) and to a lesser extent Bcl-2, while Bax and FLICE inhibitory protein (FLIP) remained unchanged. In contrast, in the presence of serum FLIP was also upregulated. We conclude that under serum-free conditions, Bcl-X(L) rather than FLIP plays the main role in protection against DC apoptosis.

Hepatic Stellate Cells Undermine the Allostimulatory Function of Liver Myeloid Dendritic Cells via STAT3-Dependent Induction of IDO

“…Unlike other hematopoietic cells, DCs are resistant to Fas/FasL-induced apoptosis (51, 52). Indeed, Fas/FasL interactions can induce DC maturation (51, 53), increase IL-1β secretion (53) and inhibit DC apoptosis via NFκB activation (53).…”

Dendritic Cell Apoptosis and the Pathogenesis of Dengue

“…It has been suggested that DENV-induced DC apoptosis is dependent on viral infection and replication [15,52]. However, it was recently demonstrated that bystander apoptosis of DENV-uninfected DCs is strain dependent and that TNF-α secreted during DENV infection protects DCs from apoptosis [15], possibly by inducting DCs maturation [117]. Some viruses, such as Foot and Mouth Disease Virus (FMDV) can even induce DC apoptosis and affect its functions before the infection, as shown for murine Bone Marrow Derived DCs (BMDCs).…”

Adoptive Transfer of Dendritic Cells Expressing Fas Ligand Modulates Intestinal Inflammation in a Model of Inflammatory Bowel Disease

“…Furthermore, Annexin V-positivity, an indicator of apoptosis, was much greater in FasL-DCs/CD4 + T cell cocultures than in cocultures containing EV-DCs ( Figure 2C , and Supplemental Figure 2 ). Even though mature DCs have been shown to express Fas, studies have demonstrated that they have an increased expression of anti-apoptotic molecules such as c-FLIP and Bcl-xL, probably leading to their protection from apoptosis [ 30 – 32 ]. Therefore, FasL-DCs attenuate T cell inflammatory cytokine production in vitro likely by inducing T cell apoptosis.…”