Prep1/Pbx2 complexes regulate CCL2 expression through the -2578 guanine polymorphism

Genes Immun. 2008 Jul;9(5):419-30. doi: 10.1038/gene.2008.33. Epub 2008 May 15.


CC-chemokine ligand 2 (CCL2) is the major chemoattractant protein that recruits monocytes to sites of inflammation and increased expression of CCL2 is associated with numerous inflammatory diseases including human immunodeficiency virus-associated dementia (HIV-D). The -2578 guanine polymorphism in the CCL2 promoter has been associated with increased expression of CCL2 as well as pathogenesis of HIV-D; however, the molecular mechanism of regulation is unknown. We propose a molecular model for -2578 G-regulated CCL2 expression in astrocytes, which are major producers of CCL2 in the brain. The -2578 G polymorphism creates a consensus-binding site for the transcriptional regulator Prep1, which along with binding partner Pbx2, preferentially binds the -2578 G allele. CCL2 promoters harboring the G allele under unstimulated conditions exhibit a lower basal activity compared to the ancestral A allele. Upon interleukin-1 beta stimulation, Prep1/Pbx2 complexes maintain the ability to bind -2578 G alleles, yet transcription levels from promoters that harbor the A or G allele are equally activated, suggesting that the -2578 region does not influence CCL2 transcription under proinflammatory conditions. Therefore, promoters that harbor the -2578 G allele undergo a higher fold induction and by extension, individuals homozygous for -2578 G would be expected to exhibit hyper-responsive CCL2 phenotypes during periods of inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Blotting, Western
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism*
  • Guanine*
  • Homeodomain Proteins / genetics*
  • Humans
  • Molecular Sequence Data
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics*


  • Chemokine CCL2
  • Homeodomain Proteins
  • PBX2 protein, human
  • PKNOX1 protein, human
  • Proto-Oncogene Proteins
  • Guanine