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STAT6 and Ets-1 form a stable complex that modulates Socs-1 expression by interleukin-4 in keratinocytes

Julia Travagli1, Martine Letourneur, Jacques Bertoglio

  • 1INSERM U461, Faculté de pharmacie, 5 Rue J. B. Clément, 92296-Chatenay-Malabry, France.

The Journal of Biological Chemistry
|June 17, 2004
PubMed

Insights

Interleukin-4 (IL-4) regulates Suppressor of Cytokine Signaling-1 (SOCS-1) gene expression in skin cells via a specific DNA element. This element involves STAT6 and Ets transcription factors, crucial for controlling inflammatory responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Dermatology

Background:

  • Suppressor of cytokine signaling (SOCS)-1 modulates immune responses by inhibiting the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway.
  • Interleukin-4 (IL-4) is known to up-regulate SOCS-1 expression in keratinocytes, but the regulatory mechanisms are not fully understood.

Purpose of the Study:

  • To identify the specific DNA sequences in the 5'-flanking region of the SOCS-1 gene that are responsive to IL-4.
  • To elucidate the transcription factors involved in IL-4-mediated regulation of SOCS-1 in keratinocytes.

Main Methods:

  • Cloning and promoter analysis of the 5'-flanking region of the SOCS-1 gene.
  • Site-directed mutagenesis to identify functional elements and transcription factor binding sites.
  • Luciferase reporter assays to assess gene expression.
  • Co-immunoprecipitation to study protein-protein interactions.

Main Results:

  • A functional IL-4-responsive element was identified at nucleotide (-684/-570) upstream of the SOCS-1 transcription initiation site.
  • This element contains binding sites for STAT6 and Ets transcription factors; mutations abolished IL-4 responsiveness.
  • Ets-1 physically interacted with STAT6, and co-expression inhibited SOCS-1 promoter activity.

Conclusions:

  • STAT6 and Ets transcription factors, acting through a composite DNA element, are critical for IL-4-induced SOCS-1 gene expression in keratinocytes.
  • These findings reveal a novel regulatory mechanism for SOCS-1, impacting cytokine signaling and immune responses in the skin.

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