IL-2 gene expression and NF-kappa B activation through CD28 requires reactive oxygen production by 5-lipoxygenase.
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.
Los
M
M
Institute of Biochemistry, Albert-Ludwigs-University, Freiburg, Germany.
Schenk
H
H
Hexel
K
K
Baeuerle
P A
PA
Dröge
W
W
Schulze-Osthoff
K
K
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D001483:Base Sequence; D016227:Benzoquinones; D018106:CD28 Antigens / Q000378:metabolism*; D002455:Cell Division; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054467:Phospholipases A2; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism
D016227:Benzoquinones; D018106:CD28 Antigens; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D011809:Quinones; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D007975:Leukotriene B4; D017828:Rifabutin; D016718:Arachidonic Acid; C020754:herbimycin; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase; D011505:Protein-Tyrosine Kinases; D010741:Phospholipases A; D054467:Phospholipases A2