Tsuboi Isao, Harada Tomonori, Hirabayashi Yoko, Kanno Jun, Aizawa Shin
Division of Anatomical Science, Department of Functional Morphology, Nihon University School of Medicine.
Biol Pharm Bull. 2016;39(12):1939-1947. doi: 10.1248/bpb.b16-00375.
Chronic lipopolysaccharide (LPS) exposure to mice reduces the lymphoid compartment and skews the hematopoietic cell compartment toward myeloid-cells, which is considered to be a direct effect of LPS on hematopoietic stem cells. However, the effect of chronic LPS exposure on stromal-cells, which compose the hematopoietic microenvironment, has not been elucidated. Here, we investigated early- and late-phase effects of repeated LPS exposure on stromal-cells. During the early phase, when mice were treated with 5 or 25 µg LPS three times at weekly intervals, the numbers of myeloid-progenitor (colony forming unit-granulocyte macrophage (CFU-GM)) cells and B lymphoid-progenitor (CFU-preB) cells in the bone-marrow (BM) rapidly decreased after each treatment. The number of CFU-GM cells recovered from the initial decrease and then increased to levels higher than pretreatment levels, whereas the number of CFU-preB cells remained lower than pretreatment levels. In the BM, expression of genes for positive-regulators of myelopoiesis including granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-6 and negative-regulators of B lymphopoiesis including tumor necrosis factor (TNF)-α was up-regulated, whereas expression of positive-regulators of B lymphopoiesis including stromal cell-derived factor (SDF)-1, IL-7, and stem cell factor (SCF) was down-regulated. During the late phase, the number of CFU-preB cells remained lower than pretreatment levels 70 d after the first treatments with 5 and 25 µg LPS, whereas the number of CFU-GM cells returned to pretreatment levels. IL-7 gene expression in the BM remained down-regulated, whereas gene-expression levels of SDF-1 and SCF were restored. Thus, chronic LPS exposure may impair stromal-cell function, resulting in prolonged suppression of B lymphopoiesis, which may appear to be senescence similar to the hematological phenotype.
长期给小鼠注射脂多糖（LPS）会减少淋巴样细胞区室，并使造血细胞区室向髓样细胞倾斜，这被认为是LPS对造血干细胞的直接作用。然而，长期LPS暴露对构成造血微环境的基质细胞的影响尚未阐明。在此，我们研究了反复LPS暴露对基质细胞的早期和晚期影响。在早期，当小鼠每周接受3次5或25μg LPS治疗时，每次治疗后骨髓（BM）中的髓样祖细胞（集落形成单位-粒细胞巨噬细胞（CFU-GM））和B淋巴样祖细胞（CFU-preB）数量迅速减少。CFU-GM细胞数量从最初的减少中恢复，然后增加到高于预处理水平，而CFU-preB细胞数量仍低于预处理水平。在BM中，包括粒细胞集落刺激因子（G-CSF）、粒细胞巨噬细胞集落刺激因子（GM-CSF）和白细胞介素（IL）-6在内的髓系造血正调节因子以及包括肿瘤坏死因子（TNF）-α在内的B淋巴细胞生成负调节因子的基因表达上调，而包括基质细胞衍生因子（SDF）-1、IL-7和干细胞因子（SCF）在内的B淋巴细胞生成正调节因子的表达下调。在晚期，首次用5和25μg LPS治疗70天后，CFU-preB细胞数量仍低于预处理水平，而CFU-GM细胞数量恢复到预处理水平。BM中IL-7基因表达仍下调，而SDF-1和SCF的基因表达水平恢复。因此，长期LPS暴露可能损害基质细胞功能，导致B淋巴细胞生成长期受到抑制，这可能表现为类似于血液学表型的衰老。
