Prep1/Pbx2 complexes regulate CCL2 expression through the -2578 guanine polymorphism.
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.
Wright
E K
EK
McKusick-Nathans Institute of Genetic Medicine, Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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Barber
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Clements
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D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D006147:Guanine; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D018932:Chemokine CCL2; D018398:Homeodomain Proteins; C090465:PBX2 protein, human; C106682:PKNOX1 protein, human; D011518:Proto-Oncogene Proteins; D006147:Guanine