Therapeutic Approach for Allergic or Autoimmune Diseases by Modulation of CD25+CD4+ T Cells

虽然紫外线B（UVB）诱导树突状细胞（DC），如朗格汉斯细胞（LC）的凋亡和功能紊乱，但它也刺激一些LC在体内照射后成熟。为了分析其对DC的相互作用，我们使用人单核细胞衍生的DC（MoDC）在体外阐明UVB对DC的直接作用。UVB从50到200 J/m^2刺激MoDC成熟，1）增加共刺激分子如CD 86和HLA-DR的表达，2）在mRNA和蛋白水平上增加IL-1β、IL-6、IL-8、IL-10和TNF-α的产生，3）在每个细胞的基础上增加同种异体刺激能力，而超过的剂量诱导凋亡性细胞死亡。UVB照射后MoDCs的Western-blot分析显示p38和c-JUN N-末端激酶（JNK）-丝裂原活化蛋白激酶（MAPK）的磷酸化呈剂量依赖性，但细胞外信号调节激酶（ERK）的磷酸化不明显。P38 MAPK抑制剂SB 203580可抑制UVB诱导的MoDCs成熟和凋亡。有趣的是，已经经历凋亡的MoDC表现出HLA-DR的表达增加，而没有CD 86抗原的上调，这表明它们的致耐受表型。因此，我们的研究揭示了UVB的双重作用，刺激成熟或诱导凋亡的MoDC，这取决于剂量，主要是通过p38 MAPK途径。

Although ultraviolet B (UVB) induces apoptosis and functional perturbations in dendritic cells (DCs), e.g. Langerhans cells (LCs), it also stimulates some LCs into maturation after irradiation in vivo. To analyze its reciprocal effects on DCs, we elucidated the direct effect of UVB on DCs in vitro using human monocyte-derived DCs (MoDCs). UVB from 50 to 200 J/m^2 stimulated the maturation of MoDCs with 1) augmented expression of co-stimulatory molecules such as CD86 and HLA-DR, 2) enhanced production of IL-1β, IL-6, IL-8, IL-10 and TNF-α 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 MoDCs after UVB demonstrated a dose-dependent phosphorylation of p38-and c-JUN N-terminal kinase (JNK)-mitogen-activated protein kinases (MAPKs), but not that of extracellular signal-regulated kinases (ERK). P38 MAPK-inhibitor, SB203580, inhibited both UVB-induced maturation and apoptosis of MoDCs. Interestingly, MoDCs that had undergone apoptosis exhibited an augmented expression of HLA-DR without up-regulation of CD86 antigen, suggesting their tolerogenic phenotype. Thus, our study revealed a dual effect of UVB, to stimulate maturation or to induce apoptosis in MoDCs, depending on the dosage, mainly via the p38 MAPK-pathway.