Dendritic Cell Survival and Maturation Are Regulated by Different Signaling Pathways

Abstract

Although dendritic cell (DC) activation is a critical event for the induction of immune responses, the signaling pathways involved in this process have not been characterized. In this report, we show that DC activation induced by lipopolysaccharide (LPS) can be separated into two distinct processes: first, maturation, leading to upregulation of MHC and costimulatory molecules, and second, rescue from immediate apoptosis after withdrawal of growth factors (survival). Using a DC culture system that allowed us to propagate immature growth factor–dependent DCs, we have investigated the signaling pathways activated by LPS. We found that LPS induced nuclear translocation of the nuclear factor (NF)-κB transcription factor. Inhibition of NF-κB activation blocked maturation of DCs in terms of upregulation of major histocompatibility complex and costimulatory molecules. In addition, we found that LPS activated the extracellular signal–regulated kinase (ERK), and that specific inhibition of MEK1, the kinase which activates ERK, abrogated the ability of LPS to prevent apoptosis but did not inhibit DC maturation or NF-κB nuclear translocation. These results indicate that ERK and NF-κB regulate different aspects of LPS-induced DC activation: ERK regulates DC survival whereas NF-κB is responsible for DC maturation.

A new carboxamide compound exerts immuno‐suppressive activity by inhibiting dendritic cell maturation

“…TLR, IL-1R, TNF and CD40 receptors lead to activation of downstream signaling cascades such as the NF-jB pathway or the MAP kinase pathways [35]. Thus, it was reported that the ERK1/2 and PI3K pathways were involved in DC survival, whereas the p38 MAPK and the NF-jB pathways were critical for DC maturation [21,36,37]. We have previously shown that JM34 inhibited the PKC-dependent activation of ERK2 in macrophages [18], but this is unlikely to account for the present inhibition of DC maturation.…”

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…We questioned whether the EPO treatment of BM-DCs activates signal transduction pathways that participate in DC activation (Lindner et al, 2007;Rescigno et al, 1998) 13 and thus focused on the NF-κB, MAPK and AKT pathways. BM-DCs were stimulated with 50 U/ml rHuEPO or with 0.05 µg/ml LPS (positive control) for the indicated time periods and cell lysates were subjected to immunoblot analysis.…”

“…We showed that EPO-Rstimulation in the BM-DCs activated the MAPK, AKT and NF-κB pathways. These pathways are crucial for the maturation and survival of DCs (Rescigno et al, 1998).…”

NF-κB and the regulation of hematopoiesis

“…Blocking LPS-induced NF-kB activation by the application of TPCK blocks the maturation process of these cells. 28 In addition, pretreatment of DCs with PSI, an irreversible proteasome inhibitor, decreases the antigen-presenting function of these cells. 29 As discussed above, it is clear that NF-kB proteins play a crucial role in DC maturation.…”