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An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response

Chundong Yu1, Brian York, Shu Wang

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Molecular Cell
|March 14, 2007
PubMed

Insights

Steroid receptor coactivator-3 (SRC-3) deficiency enhances inflammatory responses and hypersensitivity to endotoxic shock. SRC-3 acts as a crucial translational repressor of inflammatory cytokines, protecting against severe inflammation.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cellular Biology

Background:

  • Steroid receptor coactivator-3 (SRC-3) is a known transcriptional coactivator.
  • Its role in inflammation and its impact on cytokine regulation are not well understood.

Purpose of the Study:

  • To investigate the role of SRC-3 in the inflammatory process, particularly in response to lipopolysaccharide (LPS).
  • To determine if SRC-3 influences cytokine production at the transcriptional or translational level.

Main Methods:

  • Utilized SRC-3 knockout (SRC-3-/-) mice and wild-type controls.
  • Administered LPS to induce endotoxic shock and analyzed inflammatory responses.
  • Quantified pro-inflammatory cytokine production (TNF-alpha, IL-6, IL-1beta) and their corresponding mRNA levels in macrophages.
  • Assessed cytokine mRNA localization on polysomes to infer translational regulation.

Main Results:

  • SRC-3-/- mice exhibited heightened sensitivity to LPS-induced endotoxic shock.
  • SRC-3-/- macrophages produced significantly higher levels of pro-inflammatory cytokines compared to wild-type controls.
  • Cytokine mRNA levels were similar between SRC-3-/- and wild-type macrophages, indicating post-transcriptional regulation.
  • Increased association of TNF-alpha and IL-1beta mRNAs with heavy polysomes in SRC-3-/- macrophages suggests SRC-3 acts as a translational repressor.

Conclusions:

  • SRC-3 plays a critical role in regulating the translation of inflammatory cytokine mRNAs.
  • SRC-3 functions as a translational repressor, potentially cooperating with factors like TIA-1 and TIAR.
  • SRC-3 is essential for physiological protection against lethal endotoxic shock by controlling acute inflammatory responses.

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