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

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.

Redox signalling by transcription factors NF-κB and AP-1 in lymphocytes

“…It was observed recently that triggering CD28, a major co-stimulatory molecule, causes the rapid decrease of aSH within minutes and enhances ROI formation, which is maintained for 16-24 hr after cell stimulation [29,30]. This long-lasting prooxidant stimulus may explain why, in contrast to many other cell types, NF-KB activation in T cells is generally observed for a rather prolonged period.…”

“…This long-lasting prooxidant stimulus may explain why, in contrast to many other cell types, NF-KB activation in T cells is generally observed for a rather prolonged period. Inhibitor studies have demomitrated that the dioxygenase activity of 5-lipoxygenast~ is involved in inducing the prooxidant signal observed upon CD28 ligation [30].…”

“…Since neutrophils and macrophages secrete large amounts of ROIs in inflamed tissues, exogenously produced ROIs are likely to playa hormone-or mediator-like role in early T cell activation. Furthermore, activation of cultured T cells by stimulation of the TCR or co-stimulatory molecules rapidly induces an intracellular production of ROIs, as measured by the induction of H 2 0 2 production or GSH depletion [23,29,30]. The regulatory role of this ROI production is shown by the strong inhibitory effect of distinct antioxidants on the expression of cytokine genes following T cell activation.…”

Oral administration of tepoxalin in the horse: A PK/PD study

“…This causes vasoconstriction at the level of gastric mucosa and increases the formation of reactive oxygen radicals from the peroxidative cleavage of hydroxyeicosatetraenoic acids (Los et al, 1995), resulting in further mucosal injury. The gastric and intestinal mucosal lesions produced by NSAIDs can be prevented by the concurrent administration of 5-LO inhibitors (Rainsford, 1987(Rainsford, , 1993.…”

Activation of NF‐κB by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers

“…It was proposed that mitochondrial ubiquinone generates the NF-~:B-activating ROIs in response to TNF stimulation. Triggering of the CD28 receptor on T cells also results in the production of ROIs and NF-~B activation [11]. Inhibitors of 5-1ipoxygenase block NF-~B activation by CD28, suggesting that this enzyme generates the ROIs in this pathway.…”