ROS-deficient monocytes have aberrant gene expression that correlates with inflammatory disorders of chronic granulomatous disease.
Chronic granulomatous disease is an immunodeficiency caused by an inability to produce reactive oxygen species. While the mechanism of hyper-sensitivity to infection is well understood in CGD, the basis for debilitating inflammatory disorders that arise in the absence of evident infection has not been fully explained. Herein it is demonstrated that resting and TLR-activated monocytes from individuals with CGD expressed significantly higher levels of inflammatory mediators than control cells; the expression in CGD cells resembled normal cells stimulated with lipopolysaccharide. The lack of acute illness, infection or circulating endotoxin in the blood of the CGD patients at the time of sampling was consistent with infection-free inflammation. The enhanced expression of inflammatory mediators correlated with elevated expression of NF-kappaB and was dependent on ERK1/2 signalling. The results are consistent with the hypothesis that ROS are anti-inflammatory mediators that control gene expression and potentially limit the development of sterile inflammatory disorders.
Brown
Kelly L
KL
Centre for Microbial Disease Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada. klbrown@interchange.ubc.ca
Bylund
Johan
J
MacDonald
Kelly L
KL
Song-Zhao
George X
GX
Elliott
Melissa R
MR
Falsafi
Reza
R
Hancock
Robert E W
RE
Speert
David P
DP
D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D018836:Inflammation Mediators; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase