Department of Medicine, Division of Immunology and Rheumatology, Stanford University, USA.
Clin Immunol. 2012 Apr;143(1):73-82. doi: 10.1016/j.clim.2012.01.007. Epub 2012 Jan 28.
In rheumatoid arthritis (RA), hematopoietic progenitor cells (HPC) have age-inappropriate telomeric shortening suggesting premature senescence and possible restriction of proliferative capacity. In response to hematopoietic growth factors RA-derived CD34(+) HPC expanded significantly less than age-matched controls. Cell surface receptors for stem cell factor (SCF), Flt 3-Ligand, IL-3 and IL-6 were intact in RA HPC but the cells had lower transcript levels of cell cycle genes, compatible with insufficient signal strength in the ERK pathway. Cytokine-induced phosphorylation of ERK1/2 was diminished in RA HPC whereas phosphorylated STAT3 and STAT5 molecules accumulated to a similar extent as in controls. Confocal microscopy demonstrated that the membrane-proximal colocalization of K-Ras and B-Raf was less efficient in RA-derived CD34(+) cells. Thus, hyporesponsiveness of RA HPC to growth factors results from dampening of the ERK signaling pathways; with a defect localized in the very early steps of the ERK signaling cascade.
在类风湿关节炎 (RA) 中，造血祖细胞 (HPC) 具有不适当的端粒缩短，提示过早衰老和增殖能力可能受限。RA 来源的 CD34(+) HPC 对造血生长因子的反应明显小于年龄匹配的对照，扩增幅度显著较小。RA HPC 中干细胞因子 (SCF)、Flt3 配体、IL-3 和 IL-6 的细胞表面受体完整，但细胞周期基因的转录水平较低，与 ERK 通路中的信号强度不足一致。RA HPC 中的 ERK1/2 细胞因子诱导磷酸化减少，而磷酸化 STAT3 和 STAT5 分子的积累与对照相似。共聚焦显微镜显示，RA 衍生的 CD34(+) 细胞中 K-Ras 和 B-Raf 的膜近端共定位效率较低。因此，RA HPC 对生长因子的低反应性源于 ERK 信号通路的抑制；该缺陷定位于 ERK 信号级联的早期步骤。
