TNF-alpha upregulates the A2B adenosine receptor gene: The role of NAD(P)H oxidase 4

Biochem Biophys Res Commun. 2008 Oct 24;375(3):292-6. doi: 10.1016/j.bbrc.2008.07.059. Epub 2008 Jul 21.


Proliferation of vascular smooth muscle cells (VSMC), oxidative stress, and elevated inflammatory cytokines are some of the components that contribute to plaque formation in the vasculature. The cytokine tumor necrosis factor-alpha (TNF-alpha) is released during vascular injury, and contributes to lesion formation also by affecting VSMC proliferation. Recently, an A(2B) adenosine receptor (A(2B)AR) knockout mouse illustrated that this receptor is a tissue protector, in that it inhibits VSMC proliferation and attenuates the inflammatory response following injury, including the release of TNF-alpha. Here, we show a regulatory loop by which TNF-alpha upregulates the A(2B)AR in VSMC in vitro and in vivo. The effect of this cytokine is mimicked by its known downstream target, NAD(P)H oxidase 4 (Nox4). Nox4 upregulates the A(2B)AR, and Nox inhibitors dampen the effect of TNF-alpha. Hence, our study is the first to show that signaling associated with Nox4 is also able to upregulate the tissue protecting A(2B)AR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Gene Expression Regulation*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • NADPH Oxidase 4
  • NADPH Oxidases / physiology*
  • Promoter Regions, Genetic
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Receptor, Adenosine A2A / genetics*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation


  • Reactive Oxygen Species
  • Receptor, Adenosine A2A
  • Tumor Necrosis Factor-alpha
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse