A distal enhancer in II12b is the target of transcriptional repression by the STAT3 pathway and requires the basic leucine zipper (B-ZIP) protein NFIL3

Amber Smith, Joseph E. Qualls, Kevin O'Brien, Liza Balouzian, Peter F. Johnson, Stacey Schultz-Cherry, Stephen T. Smale, Peter J. Murray

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)23582-23590
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number26
DOIs
StatePublished - Jul 1 2011

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Leucine Zippers
STAT3 Transcription Factor
Interleukin-3
Myeloid Cells
Nuclear Proteins
Interleukin-10
Interleukin-23
Interleukin-12
Basic-Leucine Zipper Transcription Factors
Interleukin-12 Subunit p40
T-cells
Autoimmune Diseases
Anti-Inflammatory Agents
Cytokines
T-Lymphocytes
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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A distal enhancer in II12b is the target of transcriptional repression by the STAT3 pathway and requires the basic leucine zipper (B-ZIP) protein NFIL3. / Smith, Amber; Qualls, Joseph E.; O'Brien, Kevin; Balouzian, Liza; Johnson, Peter F.; Schultz-Cherry, Stacey; Smale, Stephen T.; Murray, Peter J.

In: Journal of Biological Chemistry, Vol. 286, No. 26, 01.07.2011, p. 23582-23590.

Research output: Contribution to journalArticle

Smith, Amber ; Qualls, Joseph E. ; O'Brien, Kevin ; Balouzian, Liza ; Johnson, Peter F. ; Schultz-Cherry, Stacey ; Smale, Stephen T. ; Murray, Peter J. / A distal enhancer in II12b is the target of transcriptional repression by the STAT3 pathway and requires the basic leucine zipper (B-ZIP) protein NFIL3. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 26. pp. 23582-23590.
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AU - Johnson, Peter F.

AU - Schultz-Cherry, Stacey

AU - Smale, Stephen T.

AU - Murray, Peter J.

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AB - 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.

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