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Interleukin-1beta up-regulates RGS4 through the canonical IKK2/IkappaBalpha/NF-kappaB pathway in rabbit colonic

Wenhui Hu1, Fang Li, Sunila Mahavadi

  • 1Departments of Physiology and Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA. whu@vcu.edu

The Biochemical Journal
|February 12, 2008
PubMed

Insights

Interleukin-1beta increases Regulator of G-protein Signalling 4 expression via the NF-kappaB pathway, inhibiting intestinal smooth muscle contraction. This reveals a new mechanism for controlling muscle response.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Cell Signalling

Background:

  • Regulator of G-protein signalling 4 (RGS4) attenuates G(q)-coupled receptor-mediated intestinal smooth muscle contraction.
  • Interleukin-1beta (IL-1beta) inhibits acetylcholine-stimulated contraction by upregulating RGS4.
  • Nuclear Factor kappaB (NF-kappaB) signalling is the primary pathway activated by IL-1beta.

Purpose of the Study:

  • To investigate if RGS4 is a target gene of the IL-1beta/NF-kappaB signalling pathway.
  • To elucidate the mechanism by which IL-1beta regulates RGS4 expression and affects smooth muscle contraction.

Main Methods:

  • Cultured rabbit colonic muscle cells were treated with IL-1beta.
  • RGS4 mRNA expression was measured.
  • NF-kappaB pathway activation was assessed using reporter assays, DNA binding activity, protein translocation, and phosphorylation.
  • Specific inhibitors and small interfering RNA (siRNA) were used to block pathway components.
  • Phospholipase C-beta (PLC-beta) activation was measured.

Main Results:

  • IL-1beta rapidly increased RGS4 mRNA expression in a transcription-dependent manner.
  • The canonical IKK2/IkappaBalpha pathway mediated IL-1beta-induced NF-kappaB activation.
  • IL-1beta-induced RGS4 up-regulation was dependent on IKK2, IkappaBalpha, and NF-kappaB.
  • Inhibition of IKK2 or NF-kappaB blocked IL-1beta's effect on acetylcholine-stimulated PLC-beta activation.

Conclusions:

  • The canonical IKK2/IkappaBalpha/NF-kappaB pathway mediates IL-1beta-induced RGS4 expression in colonic smooth muscle.
  • This pathway contributes to IL-1beta's inhibitory effect on acetylcholine-stimulated contraction by modulating PLC-beta activation.

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