Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD).
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 D(2) (PGD(2)). In addition, during phagocytosis of opsonized and nonopsonized apoptotic targets, CGD macrophages are severely compromised in their ability to produce PGD(2) and transforming growth factor-beta (TGF-beta). We suggest that delayed apoptosis of inflammatory cells, such as neutrophils and deficient production of the anti-inflammatory mediators PGD(2) and TGF-beta during macrophage clearance of apoptotic debris and invading pathogens, contributes to persistence of inflammation in CGD.
Brown
Joanne R
JR
Immunobiology Unit, The Institute of Child Health, Great Ormond Street Hospital, University College London, United Kingdom. J.Brown@ich.ucl.ac.uk
Goldblatt
David
D
Buddle
Joanna
J
Morton
Louise
L
Thrasher
Adrian J
AJ
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D002648:Child; D002675:Child, Preschool; D015232:Dinoprostone / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D019255:NADPH Oxidases / Q000172:deficiency; D009504:Neutrophils / Q000473:pathology*; D009895:Opsonin Proteins; D010587:Phagocytosis; D015230:Prostaglandin D2 / Q000096:biosynthesis / Q000172:deficiency*; D016897:Respiratory Burst; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D009895:Opsonin Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019255:NADPH Oxidases; D015232:Dinoprostone; D015230:Prostaglandin D2