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Updated: May 5, 2026

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TNF-alpha downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding

L A Denson1, R K Menon, A Shaufl

  • 1Department of Pediatrics and Yale Child Health Research Center, Yale University School of Medicine, New Haven, Connecticut, USA. lee.denson@yale.edu

The Journal of Clinical Investigation
|June 8, 2001
PubMed

Insights

Inflammation suppresses growth hormone receptor (GHR) gene expression in mice via TNF-alpha signaling, inhibiting Sp1/Sp3 transactivators. This discovery may lead to new strategies for treating growth failure in children.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Immunology

Background:

  • Children with chronic inflammatory diseases often suffer from growth failure and wasting.
  • This may stem from growth hormone resistance, potentially caused by cytokine-induced suppression of growth hormone receptor (GHR) gene expression.

Purpose of the Study:

  • To investigate the factors governing inflammatory regulation of GHR expression.
  • To test the hypothesis that TNF-alpha suppresses GHR expression by inhibiting Sp1/Sp3 transactivators.

Main Methods:

  • Administered LPS to mice and analyzed hepatic GHR expression and Sp1/Sp3 binding to the GHR promoter.
  • Utilized TNF receptor 1-deficient mice to assess the role of TNF-alpha.
  • Treated BNL CL.2 mouse liver cells with TNF-alpha and analyzed GHR promoter activity using a luciferase reporter assay.

Main Results:

  • LPS administration significantly reduced hepatic GHR expression and Sp1/Sp3 binding to GHR promoter cis elements in wild-type mice.
  • LPS did not affect hepatic Sp1/Sp3 binding or GHR expression in TNF receptor 1-deficient mice, highlighting TNF-alpha's integral role.
  • TNF-alpha treatment reduced Sp1/Sp3 binding and GHR promoter activity in liver cells; mutations in Sp elements abolished this suppression.

Conclusions:

  • Murine GHR transcription is downregulated by LPS, primarily through TNF-alpha-dependent signaling.
  • Inhibition of Sp transactivator binding to the GHR promoter is implicated in this downregulation.
  • Understanding these mechanisms could reveal novel strategies to prevent inflammatory suppression of growth.

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