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

E. K. Wright, S. H. Page, S. A. Barber, J. E. Clements

Research output: Contribution to journalArticle

Abstract

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-1β 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.

Original languageEnglish (US)
Pages (from-to)419-430
Number of pages12
JournalGenes and immunity
Volume9
Issue number5
DOIs
StatePublished - Jul 1 2008

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

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