Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis.
OBJECTIVE
Corticosteroids are used in sepsis treatment to benefit outcome. However, discussion remains on which patients will benefit from treatment. Inter-individual variations in cortisol sensitivity, mediated through the glucocorticoid receptor, might play a role in the observed differences. Our aim was to study changes in mRNA levels of three glucocorticoid receptor splice variants in neutrophils of children with sepsis.


METHODS
Twenty-three children admitted to the pediatric intensive care unit with sepsis or septic shock were included. Neutrophils were isolated at days 0, 3 and 7, and after recovery (>3 months). mRNA levels of the glucocorticoid receptor splice variants GR-alpha (determining most of the cortisol effect), GR-P (increasing GR-alpha effect) and GR-beta (inhibitor of GR-alpha) were measured quantitatively.


RESULTS
Neutrophils from sepsis patients showed decreased levels of glucocorticoid receptor mRNA of the GR-alpha and GR-P splice variants on day 0 compared to after recovery. GR-alpha and GR-P mRNA levels showed a gradual recovery on days 3 and 7 and normalized after recovery. GR-beta mRNA levels did not change significantly during sepsis. GR expression was negatively correlated to interleukin-6 (a measure of disease severity, r = -0.60, P = 0.009).


CONCLUSIONS
Children with sepsis or septic shock showed a transient depression of glucocorticoid receptor mRNA in their neutrophils. This feature may represent a tissue-specific adaptation during sepsis leading to increased cortisol resistance of neutrophils. Our study adds to understanding the mechanism of cortisol sensitivity in immune cells. Future treatment strategies, aiming at timing and tissue specific regulation of glucocorticoids, might benefit patients with sepsis or septic shock.
van den Akker
Erica L T
EL
Division of Pediatric Endocrinology, Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands. e.l.t.vandenakker@erasmusmc.nl
Koper
Jan W
JW
Joosten
Koen
K
de Jong
Frank H
FH
Hazelzet
Jan A
JA
Lamberts
Steven W J
SW
Hokken-Koelega
Anita C S
AC
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005938:Glucocorticoids / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D015278:Intensive Care Units, Pediatric; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D009504:Neutrophils / Q000378:metabolism*; D012333:RNA, Messenger / Q000097:blood / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012772:Shock, Septic / Q000188:drug therapy / Q000503:physiopathology*; D055815:Young Adult
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid