DNA methylation and the expression of IL-4 and IFN-gamma promoter genes in patients with bronchial asthma

J Clin Immunol. 2008 Mar;28(2):139-46. doi: 10.1007/s10875-007-9148-1. Epub 2007 Nov 14.


Although CpG methylation is thought to be a negative regulator of gene transcription, its relationship with cytokine expression remains unclear. Interleukin (IL)-4 and interferon (IFN)-gamma are major cytokines that affect the differentiation of naïve CD4+ T lymphocytes into the Th1 and Th2 lineage. We used bisulfite deoxyribonucleic acid modification and sequencing to examine the relationship between CpG methylation and IL-4 and IFN-gamma gene expression before and after allergen stimulation in human CD4+ T lymphocytes from sensitized hosts. In naïve cells, the CpGs in the promoter regions were methylated largely in both the IL-4 and IFN-gamma genes. After Dermatophagoides pteronyssinus/Dermatophagoides farinae stimulation, the degree of unmethylation in the IL-4 gene increased in cells from patients with bronchial asthma. After phytohemagglutinin stimulation, the degree of unmethylation increased in cells from nonallergic control subjects. The concentration of IL-4 was strongly correlated with the degree of unmethylation in the patient group. These data suggest that CpGs located at -80 of the IL-4 gene and at -295, -186, and +122 of the IFN-gamma gene have regulatory activities important for cytokine expression. We conclude that the stimulation of CD4+ T lymphocytes causes considerable increases in the degree of unmethylation and that in sensitized hosts, the extent of unmethylation correlates with the concentration of IL-4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, Dermatophagoides / immunology
  • Antigens, Dermatophagoides / pharmacology
  • Asthma / genetics*
  • Asthma / pathology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • DNA Methylation*
  • Female
  • Gene Expression / drug effects
  • Humans
  • Interferon-gamma / genetics*
  • Interleukin-4 / genetics*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Phytohemagglutinins / pharmacology
  • Promoter Regions, Genetic / genetics*


  • Antigens, Dermatophagoides
  • IL4 protein, human
  • Phytohemagglutinins
  • Interleukin-4
  • Interferon-gamma