Mechanisms of asthma and allergic inflammation
Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients

https://doi.org/10.1016/j.jaci.2004.03.018Get rights and content

Background

Most chronic inflammatory diseases are well controlled by glucocorticoids. However, a minority of patients fails to respond adequately to this treatment.

Objective

We wished to determine whether glucocorticoid insensitivity in a group of steroid-resistant (SR) and steroid-dependent (SD) asthmatic subjects resulted from an inability of the glucocorticoid receptor (GR) to translocate into the nucleus.

Methods

Glucocorticoid receptor nuclear translocation was determined in PBMCs by immunocytochemistry and GR function measured by suppression of TNF-α–induced GM-CSF release and effects of dexamethasone on histone acetylation.

Results

Glucocorticoid repression of TNF-α–induced GM-CSF release was reduced in PBMCs from SD and SR patients. This inhibition correlated with a failure of GR to translocate into the nucleus and induce histone acetylation in response to dexamethasone. In addition, dexamethasone failed to inhibit TNF-α–induced histone acetyltransferase activity, which predominantly targeted histone residues lysine (K)8 and K12. However, in a subset of patients, even high levels of GR nuclear translocation failed to produce histone acetylation in response to dexamethasone. Histone H4 K5 acetylation, a marker of dexamethasone transactivation, was specifically reduced in this group. However, cells from this subset of steroid-insensitive subjects were still capable of inhibiting TNF-α–induced histone acetylation.

Conclusion

We have identified a novel mechanism of glucocorticoid insensitivity in a group of SR and SD subjects. These data suggest that most patients respond to glucocorticoids according to the degree of GR nuclear translocation occurring, but some subjects with steroid resistance have a reduced response because of a failure of steroids to transactivate, rather than transrepress.

Section snippets

Patients

Six glucocorticoid-sensitive subjects (SS; controlled on inhaled steroids), 11 glucocorticoid-dependent asthmatic subjects (SD; controlled only on oral steroids), 9 steroid-resistant asthmatic subjects who showed no response even to high doses of oral steroids (SR), and 10 normal nonasthmatic control subjects were studied (Table I). All subjects were matched for age, and no current smokers were included in the study. The SD (2.7 ± 2 pack years) and SR (0.1 ± 0.2 pack years) groups included some

Effect of dexamethasone on TNF-α–induced GM-CSF production in PBMCs

The basal levels of GM-CSF production from PBMCs (106 cells) from normal subjects and SS, SD, and SR patients were similar in all groups. GM-CSF release was enhanced by TNF-α (10 ng/mL) in all groups to a similar extent (normal, 124 ± 10; SS, 137 ± 25; SD, 164 ± 17; SR, 103 ± 9 pg/mL). Dexamethasone (10−6 mol/L) inhibited TNF-α–induced GM-CSF production in all subject groups according to the in vivo efficacy of glucocorticoids in each subject group. Dexamethasone produced a similar level of

Discussion

PBMCs from SD and SR patients had a reduced ability to suppress TNF-α–induced GM-CSF release compared with normal and SS subjects. In most SD and SR subjects, this failure to attenuate GM-CSF release was correlated with a reduced ability of GR to translocate to the nucleus and induce histone acetylation in response to dexamethasone. These subjects were also unable to repress TNF-α–induced histone acetylation (group 1). In addition, we have also identified a distinct subgroup within SD and SR

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    Supported by the Wellcome Trust, the National Asthma Campaign, the Clinical Research Committee (Royal Brompton Hospital), and GlaxoSmithKline (United Kingdom).

    a

    These authors contributed equally to this work.

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