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

Genes & Immunity volume 9, pages 419–430 (2008)Cite this article

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.

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Acknowledgements

We thank the entire Retrovirus Laboratory at Johns Hopkins University School of Medicine for useful discussions, especially to Susan Follstaedt for her expertise with western blots, and Justyna Dudaronek and Kenneth Witwer for their expertise with siRNAs. This research was supported by NIH grants to JEC (nos. NS050028, NS47984 and MH70306).

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Authors and Affiliations

  1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    E K Wright Jr & S H Page

  2. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    E K Wright Jr, S H Page & J E Clements

  3. Booz Allen Hamilton, Rockville, MD, USA

    S A Barber

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Correspondence to J E Clements.

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Wright, E., Page, S., Barber, S. et al. Prep1/Pbx2 complexes regulate CCL2 expression through the −2578 guanine polymorphism. Genes Immun 9, 419–430 (2008). https://doi.org/10.1038/gene.2008.33

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