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(Journal of Leukocyte Biology. 2003;73:591-599.)
© 2003 by Society for Leukocyte Biology

Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD)

Joanne R. Brown^*, David Goldblatt^*, Joanna Buddle, Louise Morton and Adrian J. Thrasher

^* Immunobiology and
Molecular Immunology Units, The Institute of Child Health, and
Department of Immunology, Great Ormond Street Hospital, University College London, United Kingdom

Correspondence: Joanne R. Brown, Immunobiology Unit, The Institute of Child Health, Great Ormond Street Hospital, University College London, 30 Guilford Street, London, WC1N 1EH, UK. E-mail: J.Brown{at}ich.ucl.ac.uk

Genetic defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme system result in chronic granulomatous disease (CGD). In addition to recurrent, life-threatening infections, patients with CGD frequently present with sterile inflammatory complications, suggesting that NADPH-oxidase deficiency predisposes to these responses in the absence of persistent microbial infection. The mechanisms involved in the aberrant, inflammatory process are unknown. In this study, we have shown that neutrophils isolated from CGD patients, which are more resistant to spontaneous apoptosis in vitro, also produce significantly less of the anti-inflammatory mediator cyclopentenone prostaglandin D₂ (PGD₂). In addition, during phagocytosis of opsonized and nonopsonized apoptotic targets, CGD macrophages are severely compromised in their ability to produce PGD₂ and transforming growth factor-ß (TGF-ß). We suggest that delayed apoptosis of inflammatory cells, such as neutrophils and deficient production of the anti-inflammatory mediators PGD₂ and TGF-ß during macrophage clearance of apoptotic debris and invading pathogens, contributes to persistence of inflammation in CGD.

Key Words: inflammation • reactive oxygen species • prostaglandins

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