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Comparative Study
. 2009 Jul;35(7):1247-54.
doi: 10.1007/s00134-009-1468-6. Epub 2009 Apr 17.

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis

Erica L T van den Akker  1 , Jan W Koper, Koen Joosten, Frank H de Jong, Jan A Hazelzet, Steven W J Lamberts, Anita C S Hokken-Koelega
Affiliations
Comparative Study

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis

Erica L T van den Akker et al. Intensive Care Med. 2009 Jul.

Abstract

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.

Patients and design: 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.

Main 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.

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Figures

Fig. 1
Fig. 1
Levels of glucocorticoid receptor splice variants GR-α, GR-P, and GR-β mRNA in neutrophils of children with sepsis, measured at day 0, 3, 7 and after recovery (X-axis). Y-axis represents mRNA levels (copies) measured by real-time polymerase chain reaction. The dotted reference lines represent the ±2 SD of healthy adults
Fig. 2
Fig. 2
Longitudinal samples obtained from the seven sepsis patients with complete dataset for day 0, 3 and after recovery (X-axis). The Y-axis represents individual levels of glucocorticoid receptor splice variants GR-α, GR-P, and GR-β mRNA in neutrophils of these patients
Fig. 3
Fig. 3
Correlation between Interleukin-6 and GR-α mRNA levels at t = 0 and correlation between age and GR-α mRNA levels at t = 0
See this image and copyright information in PMC

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