p38 Mitogen-Activated Protein Kinase Mediates Dual Role of Ultraviolet B Radiation in Induction of Maturation and Apoptosis of Monocyte-Derived Dendritic Cells

Abstract

Although ultraviolet B (UVB) induces apoptosis and functional perturbations in dendritic cells (DC), for example, Langerhans cells (LC), it also stimulates some LC into maturation after irradiation in vivo. To analyze its reciprocal effects on DC, we elucidated the direct effect of UVB on DC in vitro using human monocyte-derived DC (MoDC). UVB from 50 to 200 J per m2 stimulated the maturation of MoDC with (1) augmented expression of CD86 and HLA-DR, (2) enhanced production of IL-1beta, IL-6, IL-8, and TNF-alpha at both the mRNA and protein levels, and (3) enhanced allostimulatory capacity on a per-cell basis, whereas the exceeded doses induced apoptotic cell death. Western-blot analysis of MoDC after UVB demonstrated a concentration-dependent phosphorylation of p38- and c-JUN N-terminal kinase (JNK)-mitogen-activated protein kinases (MAPK), but not that of extracellular signal-regulated kinases. p38 MAPK-inhibitor, SB203580, inhibited both UVB-induced maturation and apoptosis of MoDC. Interestingly, MoDC that had undergone apoptosis exhibited an augmented expression of HLA-DR without upregulation of CD86 antigen, suggesting their tolerogenic phenotype. Thus, our study revealed a dual effect of UVB, to stimulate maturation or to induce apoptosis in MoDC, depending on the dosage, via p38 MAPK pathway.

EGFR activation confers protections against UV-induced apoptosis in cultured mouse skin dendritic cells

“…When high dose of UV was irradiated (as used in this study), apoptosis or cell damage instead of maturation was induced on skin dendritic cells [4,28,29]. Using Western-blotting analysis and the experiments using a specific inhibitor for p38 MAPK, it is clarified that apoptosis of MoDC is mediated at least partly by p38 MAPK [4].…”

“…Using Western-blotting analysis and the experiments using a specific inhibitor for p38 MAPK, it is clarified that apoptosis of MoDC is mediated at least partly by p38 MAPK [4]. However, the detailed signals, especially the upstream signals, involved in this activation have not been fully uncovered.…”

“…1) and previous studies have demonstrated that MAPK plays important roles in UV-induced biological responses such as maturation and apoptosis of DCs [4,19], we next examined the effect of EGFR activation on phosphorylation of p38, ERK1/2, and SAPK/JNK. As shown in Fig.…”

“…In monocyte-derived dendritic cells (or MoDC) that activation of caspases 3, 8, and 9 is involved in the apoptotic processes. Some LCs, however, show maturation, when they are irradiated with UVB in vivo or ex vivo [4]. Thus far, the mechanisms through which UVB activates DCs have not been well studied.…”

Human Langerhans-cell activation triggered in vitro by conditionally expressed MKK6 is counterregulated by the downstream effector RelB

“…The p38 is activated by the upstream MAPK kinases MKK6 or MKK3 and is then translocated to the nucleus where it in turn phosphorylates respective target molecules. 19 Various studies proved that p38 is functionally involved in DC maturation, because addition of specific p38 inhibitors during UV-B irradiation, 20 hapten stimulation, 21 or TLR4 ligation 6 of mo-DCs resulted in impaired DC activation. Whether the specific activation of p38 MAPK is a trigger for DC maturation is not known.…”