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RECEPTORS AND SIGNAL TRANSDUCTION

Role of extracellular superoxide in neutrophil activation: interactions between xanthine oxidase and TLR4 induce proinflammatory cytokine production

¹Department of Medicine and ²Center for Free Radical Biology,University of Alabama at Birmingham, Birmingham, Alabama; ³Pole Anesthésie Réanimation du Centre Hospitalier Universitaire and ⁴Institut National de la Santé et de la Recherche Médicale, Amiens, France

Submitted 1 October 2007 ; accepted in final form 13 February 2008

Reactive oxygen species (ROS) contribute to neutrophil activation and the development of acute inflammatory processes in which neutrophils play a central role. However, there is only limited information concerning the mechanisms through which extracellular ROS, and particularly cell membrane-impermeable species, such as superoxide, enhance the proinflammatory properties of neutrophils. To address this issue, neutrophils were exposed to superoxide generating combinations of xanthine oxidase and hypoxanthine or lumazine. Extracellular superoxide generation induced nuclear translocation of nuclear factor-B (NF-B) and increased neutrophil production of the NF-B-dependent cytokines tumor necrosis factor- (TNF-) and macrophage inhibitory protein-2 (MIP-2). In contrast, there were no changes in TNF- or MIP-2 expression when neutrophils lacking Toll-like receptor-4 (TLR4) were exposed to extracellular superoxide. Immunoprecipitation, confocal microscopy, and fluorescence resonance energy transfer (FRET) studies demonstrated association between TLR4 and xanthine oxidase. Exposure of neutrophils to heparin attenuated binding of xanthine oxidase to the cell surface as well as interactions with TLR4. Heparin also decreased xanthine oxidase-induced nuclear translocation of NF-B as well as production of proinflammatory cytokines. These results demonstrate that extracellular superoxide has proinflammatory effects on neutrophils, predominantly acting through an TLR4-dependent mechanism that enhances nuclear translocation of NF-B and increases expression of NF-B-dependent cytokines.

reactive oxygen species; Toll-like receptor-4; nuclear factor-b; signal transduction; heparin; glycosaminoglycans