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Tumor necrosis factor alpha (TNF) suppresses cAMP response element (CRE) activity and nuclear CRE binding protein in

Koji Y Arai1, Katherine F Roby, Paul F Terranova

  • 1Department of Molecular and Integrative Physiology, Center for Reproductive Sciences, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.

Endocrine
|August 4, 2005
PubMed

Insights

Tumor necrosis factor (TNF) suppresses steroid secretion in Leydig cells by reducing nuclear levels of CREB (cAMP response element-binding protein). This mechanism explains how TNF impacts Leydig cell function.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Tumor necrosis factor (TNF) is known to inhibit gonadotropin-induced steroid secretion in Leydig cells.
  • The precise molecular mechanisms underlying TNF's suppressive effects on steroidogenesis remain largely unelucidated.
  • The protein kinase A (PKA) pathway is a key regulator of steroidogenic protein expression in Leydig cells.

Purpose of the Study:

  • To investigate the effects of TNF on cyclic AMP response element (CRE) activity in MA-10 mouse Leydig cells.
  • To determine the role of the PKA pathway and CREB in mediating TNF's suppression of steroidogenesis.
  • To elucidate the specific molecular mechanisms by which TNF inhibits Leydig cell steroid secretion.

Main Methods:

  • MA-10 mouse Leydig cells were transfected with a CRE-luciferase reporter construct.
  • Cells were stimulated with luteinizing hormone (LH) or 8Br-cAMP in the presence or absence of TNF.
  • Western blotting was used to assess levels of CREB and phospho-CREB in whole cell and nuclear extracts.

Main Results:

  • TNF significantly suppressed LH-stimulated and 8Br-cAMP-stimulated CRE activity.
  • TNF also inhibited CRE activity induced by a PKA expression vector.
  • While TNF did not alter total CREB or phospho-CREB levels, it decreased their nuclear presence in a time-dependent manner.
  • The suppressive effect of TNF on CRE activity was not mediated by the NF-kappaB pathway.

Conclusions:

  • TNF suppresses steroidogenesis in Leydig cells by reducing the nuclear levels of CREB and phospho-CREB.
  • The observed decrease in nuclear CREB is a primary mechanism through which TNF inhibits steroid secretion.
  • These findings provide crucial insights into the molecular regulation of Leydig cell function by inflammatory cytokines.

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