A distal enhancer in Il12b is the target of transcriptional repression by the STAT3 pathway and requires the basic leucine zipper (B-ZIP) protein NFIL3

J Biol Chem. 2011 Jul 1;286(26):23582-90. doi: 10.1074/jbc.M111.249235. Epub 2011 May 12.


Deregulated IL-12 and IL-23 production from activated myeloid lineage cells is a key driver of numerous T cell-dependent autoimmune and inflammatory diseases. IL-12 and IL-23 share a common p40 subunit encoded by Il12b, which is negatively regulated at the transcriptional level by the STAT3 (signal transducer and activator of transcription 3)-activating anti-inflammatory cytokine IL-10. We found that IL-10 targets an enhancer 10 kb upstream of the Il12b transcriptional start site. Within the enhancer, a single 10-bp site is required for the inhibitory effects of IL-10 and is bound by NFIL3 (nuclear factor, interleukin 3-regulated), a B-ZIP transcription factor. Myeloid cells lacking NFIL3 produce excessive IL-12p40 and increased IL-12p70. Thus, the STAT3-dependent expression of NFIL3 is a key component of a negative feedback pathway in myeloid cells that suppresses proinflammatory responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cells, Cultured
  • Enhancer Elements, Genetic / physiology*
  • Gene Expression Regulation / physiology*
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Interleukin-12 Subunit p40 / biosynthesis*
  • Interleukin-12 Subunit p40 / genetics
  • Mice
  • Mice, Knockout
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Transcription, Genetic / physiology*


  • Basic-Leucine Zipper Transcription Factors
  • IL10 protein, mouse
  • Interleukin-12 Subunit p40
  • Nfil3 protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Interleukin-10