Dendritic Cell Survival and Maturation Are Regulated by Different Signaling Pathways

TLDR

Although dendritic cell activation is critical for immune responses, the signaling pathways that mediate this process have not been characterized. The study demonstrates that lipopolysaccharide‑induced DC activation can be divided into maturation, marked by upregulation of MHC and costimulatory molecules, and survival, defined by protection from apoptosis after growth‑factor withdrawal. Using a culture system that propagates immature, growth‑factor–dependent DCs, the authors investigated the signaling pathways activated by LPS. LPS induces NF‑κB nuclear translocation to drive maturation, while ERK activation—blocked by MEK1 inhibition—specifically promotes survival, revealing distinct pathways for DC maturation and survival.

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.