Dampened ERK signaling in hematopoietic progenitor cells in rheumatoid arthritis

Clin Immunol. 2012 Apr;143(1):73-82. doi: 10.1016/j.clim.2012.01.007. Epub 2012 Jan 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34 / metabolism
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / physiopathology*
  • Cell Proliferation*
  • Cyclins / genetics
  • Cytokines / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Flow Cytometry
  • Gene Expression Profiling
  • Hematopoietic Cell Growth Factors / pharmacology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Interleukin-3 Receptor alpha Subunit / metabolism
  • Interleukin-6 Receptor alpha Subunit / metabolism
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology*
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-kit / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Antigens, CD34
  • Cyclins
  • Cytokines
  • Hematopoietic Cell Growth Factors
  • Interleukin-3 Receptor alpha Subunit
  • Interleukin-6 Receptor alpha Subunit
  • Proto-Oncogene Proteins c-myc
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Proto-Oncogene Proteins c-kit
  • fms-Like Tyrosine Kinase 3
  • Extracellular Signal-Regulated MAP Kinases