IL-2 gene expression and NF-kappa B activation through CD28 requires reactive oxygen production by 5-lipoxygenase

EMBO J. 1995 Aug 1;14(15):3731-40. doi: 10.1002/j.1460-2075.1995.tb00043.x.

Abstract

Activation of the CD28 surface receptor provides a major costimulatory signal for T cell activation resulting in enhanced production of interleukin-2 (IL-2) and cell proliferation. In primary T lymphocytes we show that CD28 ligation leads to the rapid intracellular formation of reactive oxygen intermediates (ROIs) which are required for CD28-mediated activation of the NF-kappa B/CD28-responsive complex and IL-2 expression. Delineation of the CD28 signaling cascade was found to involve protein tyrosine kinase activity, followed by the activation of phospholipase A2 and 5-lipoxygenase. Our data suggest that lipoxygenase metabolites activate ROI formation which then induce IL-2 expression via NF-kappa B activation. These findings should be useful for therapeutic strategies and the development of immunosuppressants targeting the CD28 costimulatory pathway.

MeSH terms

  • Arachidonate 5-Lipoxygenase / metabolism*
  • Arachidonic Acid / metabolism
  • Base Sequence
  • Benzoquinones
  • CD28 Antigens / metabolism*
  • Cell Division
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Enzyme Activation
  • Gene Expression Regulation / physiology
  • Humans
  • Interleukin-2 / metabolism*
  • Lactams, Macrocyclic
  • Leukotriene B4 / pharmacology
  • Lipoxygenase Inhibitors
  • Lymphocyte Activation
  • Molecular Sequence Data
  • NF-kappa B / physiology*
  • Phospholipases A / antagonists & inhibitors
  • Phospholipases A / metabolism
  • Phospholipases A2
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Quinones / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Receptors, Antigen, T-Cell / physiology
  • Rifabutin / analogs & derivatives
  • Signal Transduction / physiology*
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / metabolism

Substances

  • Benzoquinones
  • CD28 Antigens
  • Interleukin-2
  • Lactams, Macrocyclic
  • Lipoxygenase Inhibitors
  • NF-kappa B
  • Quinones
  • Reactive Oxygen Species
  • Receptors, Antigen, T-Cell
  • Leukotriene B4
  • Rifabutin
  • Arachidonic Acid
  • herbimycin
  • Dexamethasone
  • Arachidonate 5-Lipoxygenase
  • Protein-Tyrosine Kinases
  • Phospholipases A
  • Phospholipases A2