Monocyte chemoattractant protein-4 core promoter genetic variants influence on YY-1 affinity and plasma levels


KALAYCI Ö., BİRBEN E. , WU L., OGUMA T., Gravesande K., SUBRAMANİAM V., ...Daha Fazla

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, cilt.29, ss.750-756, 2003 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 29 Konu: 6
  • Basım Tarihi: 2003
  • Doi Numarası: 10.1165/rcmb.2003-0024oc
  • Dergi Adı: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
  • Sayfa Sayıları: ss.750-756

Özet

Monocyte chemoattractant protein-4 (MCP-4) is a CC chemokine implicated in the recruitment of eosinophils, monocytes, and T-lymphocytes in diseases of mucosal inflammation, including asthma. We tested the hypothesis that there is a genetic basis for differences in MCP-4 expression among individuals by evaluating the effects of core promoter variants on MCP-4 expression. We identified two single-nucleotide T-to-C polymorphisms in the MCP-4 core promoter that occur 896 and 887 base pairs preceding the transcription initiation site. The -887 variant alters a consensus binding motif for the transcription factor YY-1. Electrophoretic mobility shift assay demonstrated that YY-1 containing nuclear extracts from tumor necrosis factor alpha-stimulated peripheral blood mononuclear cells had greater avidity for the wild-type (YY-1 motif intact) sequence than for the variant sequence. Increasing doses of a YY-1 expression vector induced significantly greater reporter activity from MCP-4 core promoter expression constructs of the wild-type compared with the variant sequence in transient transfection experiments. The external validity of these observations was demonstrated by measuring plasma levels of MCP-4 from individuals with the alternative forms of the gene. Individuals bearing haplotypic variants of the MCP-4 core promoter that avidly bind the transcription factor YY-1 had higher plasma levels of MCP-4 than did individuals with variants with lower binding avidity (490, 360, and 360 pg/ml; P < 0.01). Our findings suggest that the MCP-4 core promoter YY-1 binding motif is functional, modulates the transcriptional regulation of the MCP-4 gene, and that part of the variance in the systemic expression of MCP-4 is determined by core promoter genetic variants.