Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFkappaB

Int Immunol. 2004 Mar;16(3):395-404. doi: 10.1093/intimm/dxh042.


Activation-induced cytidine deaminase (AID) is an inducible gene that plays an important role in class switch recombination, somatic hypermutation and gene conversion in B cells. We examined the regulation of AID gene expression in human and mouse B cells by IL-4 and CD40 ligation. IL-4 by itself and, to a much lesser extent, CD40 ligation induced AID mRNA expression in primary B cells. The two stimuli strongly synergized in inducing AID mRNA and protein expression. IL-4 induced STAT6 binding to a site in the 5' upstream region of the AID gene, while CD40 ligation induced NFkappaB binding to two sites in that region. B cells from STAT6-/- mice failed to up-regulate AID in response to IL-4, while B cells from p50-/- mice were impaired in their ability to up-regulate AID in response to CD40 ligation and IL-4. These results suggest that signals delivered via CD40 that activate NFkappaB synergize with signals delivered via the IL-4 receptor that activate STAT6 to induce optimal AID gene expression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / metabolism
  • Binding Sites
  • CD40 Antigens / metabolism*
  • Cell Culture Techniques
  • Cell Line
  • Cytidine Deaminase / biosynthesis
  • Cytidine Deaminase / genetics*
  • DNA-Binding Proteins / metabolism
  • Electrophoretic Mobility Shift Assay
  • Enzyme Induction
  • Humans
  • Interleukin-4 / metabolism
  • Interleukin-4 / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / metabolism
  • STAT6 Transcription Factor
  • Trans-Activators / metabolism*


  • CD40 Antigens
  • DNA-Binding Proteins
  • NF-kappa B
  • RNA, Messenger
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Stat6 protein, mouse
  • Trans-Activators
  • Interleukin-4
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase