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

Mol Cell. 2007 Mar 9;25(5):765-78. doi: 10.1016/j.molcel.2007.01.025.


Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator for nuclear receptors and other transcription factors. Although multiple physiological roles of SRC-3 have been revealed, its involvement in the inflammatory process remains unclear. Herein we show that SRC-3(-/-) mice are markedly hypersensitive to LPS-induced endotoxic shock. In response to LPS, SRC-3(-/-) macrophages produce significantly more proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta than wild-type controls, although they express similar amounts of cytokine mRNAs, suggesting that SRC-3 can exert effects at translational levels. Increased heavy polysome-associated TNF-alpha and IL-1beta mRNAs in SRC-3(-/-) macrophages implicate SRC-3 as a translational repressor. SRC-3 may cooperate with other translational repressors such as TIA-1 and TIAR to regulate cytokine mRNA translation. Collectively, our studies reveal an essential function of SRC-3 as a coordinator of inflammatory mRNA translation and as a physiologic protective factor against the lethal endotoxic shock triggered by an acute inflammatory response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytokines / blood
  • Cytokines / genetics*
  • Cytokines / metabolism
  • Female
  • HeLa Cells
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Inflammation*
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects
  • Male
  • Mice
  • Nuclear Receptor Coactivator 3
  • Protein Binding / drug effects
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / genetics*
  • RNA-Binding Proteins / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Repressor Proteins / metabolism
  • Shock, Septic / chemically induced
  • Shock, Septic / pathology
  • T-Cell Intracellular Antigen-1
  • Trans-Activators / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Cytokines
  • Lipopolysaccharides
  • RNA-Binding Proteins
  • Receptors, Glucocorticoid
  • Repressor Proteins
  • T-Cell Intracellular Antigen-1
  • Tia1 protein, mouse
  • Tial1 protein, mouse
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3