Dampened ERK signaling in hematopoietic progenitor cells in rheumatoid arthritis

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• 作者：Iné ; s Colmegna¹ ; Sergey Pryshchep² ; Hisashi Oishi³ ; Jö ; rg J. Goronzy ; Cornelia M. Weyand ; ^{cweyand@stanford.edu}
• 关键词：Rheumatoid arthritis ; Hematopoietic progenitor cells ; CD34 ; ERK signaling ; STAT signaling
• 刊名：Clinical Immunology
• 出版年：2012
• 期刊代码：95_15216616
• 类别：imm
• 出版时间：April, 2012
• 卷：143
• 期：1
• 页码：73-82
• 文件大小：988 K

摘要

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.