Th2 cell-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation

Lisa Cameron, Robin B. Webster, Jannine M. Strempel, Patricia Kiesler, Michael Kabesch, Harikrishnan Ramachandran, Lizhi Yu, Debra A. Stern, Penelope E. Graves, I. Carla Lohman, Anne L. Wright, Marilyn Halonen, Walter T. Klimecki, Donata Vercelli

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

IL-13 is a central mediator of allergic inflammation. The single nucleotide polymorphism IL13-1112C>T (rs1800925) is associated with allergic phenotypes in ethnically distinct populations, but the underlying mechanism(s) remain unknown. Using in vivo, in vitro, and in silico analysis, we show that the IL13-1112T allele enhanced IL13 promoter activity in primary human and murine CD4+ Th2 lymphocytes. Increased expression of IL13-1112T in Th2 cells was associated with the creation of a Yin-Yang 1 binding site that overlapped a STAT motif involved in negative regulation of IL13 expression and attenuated STAT6-mediated transcriptional repression. Because IL-13 secretion was increased in IL13-1112TT homozygotes, we propose that increased expression of IL13-1112T in vivo may underlie its association with susceptibility to allergic inflammation. Interestingly, IL13-1112T had opposite transcriptional effects in nonpolarized CD4+ T cells, paralleled by distinct patterns of DNA-protein interactions at the IL13 promoter. Our findings suggest the nuclear milieu dictates the functional outcome of genetic variation.

Original languageEnglish (US)
Pages (from-to)8633-8642
Number of pages10
JournalJournal of Immunology
Volume177
Issue number12
DOIs
StatePublished - Dec 15 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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