Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma.
BACKGROUND
The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients.


OBJECTIVE
We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function.


METHODS
PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed.


RESULTS
Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity.


CONCLUSIONS
A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult-to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population.
Emory University Department of Pediatrics, Atlanta, Ga.
Susan T
ST
Stephenson
Emory University Department of Pediatrics, Atlanta, Ga; Children's Healthcare of Atlanta Center for Cystic Fibrosis and Airways Disease Research, Atlanta, Ga.
Lou Ann S
LA
Brown
Emory University Department of Pediatrics, Atlanta, Ga; Children's Healthcare of Atlanta Center for Cystic Fibrosis and Airways Disease Research, Atlanta, Ga.
My N
MN
Helms
Emory University Department of Pediatrics, Atlanta, Ga.
Hongyan
H
Qu
Emory University Department of Pediatrics, Atlanta, Ga.
Sheena D
SD
Brown
Emory University Department of Pediatrics, Atlanta, Ga; Children's Healthcare of Atlanta Center for Cystic Fibrosis and Airways Disease Research, Atlanta, Ga.
Milton R
MR
Brown
Emory University Department of Pediatrics, Atlanta, Ga; Children's Healthcare of Atlanta Center for Cystic Fibrosis and Airways Disease Research, Atlanta, Ga. Electronic address: anne.fitzpatrick@emory.edu.
Anne M
AM
Fitzpatrick
D000280:Administration, Inhalation; D000293:Adolescent; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D002648:Child; D003545:Cysteine / Q000737:chemistry / Q000276:immunology; D003553:Cystine / Q000737:chemistry / Q000276:immunology; D016903:Drug Monitoring; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007273:Injections, Intramuscular; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D014221:Triamcinolone / Q000627:therapeutic use*
C515429:CCL3 protein, human; C475829:CXCL1 protein, human; D054405:Chemokine CCL3; D054360:Chemokine CXCL1; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014221:Triamcinolone; D003553:Cystine; D003545:Cysteine
Biomarker; childhood asthma; cysteine; inflammation; oxidative stress; refractory asthma; severe asthma; treatment response