The Journal of Experimental Medicine
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Published online 26 February 2001.
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© The Rockefeller University Press, 0022-1007/2001/3/585/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 5, March 5, 2001 585-594

Original Article

High Constitutive Glucocorticoid Receptor ß in Human Neutrophils Enables Them to Reduce Their Spontaneous Rate of Cell Death in Response to Corticosteroids

Ian Stricklanda, Kevin Kisicha, Pia J. Hauka, Alessandra Votterod, George P. Chrousosd, Dwight J. Klemmb, and Donald Y.M. Leunga,c
a Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206
b Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206
c Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262
d Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892

Correspondence to: Donald Y.M. Leung, Dept. of Pediatrics, National Jewish Medical Research Center, 1400 Jackson St., Denver, CO 80206. Tel:303-398-1186 Fax:303-270-2182 E-mail:leungd{at}njc.org.

Neutrophils are markedly less sensitive to glucocorticoids than T cells, making it difficult to control inflammation in neutrophil-mediated diseases. Development of new antiinflammatory strategies for such diseases would be aided by an understanding of mechanisms underlying differential steroid responsiveness. Two protein isoforms of the human glucocorticoid receptor (GR) exist, GR{alpha} and GRß, which arise from alternative splicing of the GR pre-mRNA primary transcripts. GRß does not bind glucocorticoids and is an inhibitor of GR{alpha} activity. Relative amounts of these two GRs can therefore determine the level of glucocorticoid sensitivity. In this study, human neutrophils and peripheral blood mononuclear cells (PBMCs) were studied to determine the relative amounts of each GR isoform.

The mean fluorescence intensity (MFI) using immunofluorescence analysis for GR{alpha} was 475 ± 62 and 985 ± 107 for PBMCs and neutrophils, respectively. For GRß, the MFI was 350 ± 60 and 1,389 ± 143 for PBMCs and neutrophils, respectively (P < 0.05). After interleukin (IL)-8 stimulation of neutrophils, there was a statistically significant increase in intensity of GRß staining to 2,497 ± 140 (P < 0.05). No change in GR{alpha} expression was observed. This inversion of the GR{alpha}/GRß ratio in human neutrophils compared with PBMCs was confirmed by quantitative Western analysis. Increased GRß mRNA expression in neutrophils at baseline, and after IL-8 exposure, was observed using RNA dot blot analysis. Increased levels of GR{alpha}/GRß heterodimers were found in neutrophils as compared with PBMCs using coimmunoprecipitation/Western analysis. Transfection of mouse neutrophils, which do not contain GRß, resulted in a significant reduction in the rate of cell death when treated with dexamethasone.

We conclude that high constitutive expression of GRß by human neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death. Moreover, upregulation of this GR by proinflammatory cytokines such as IL-8 further enhances their survival in the presence of glucocorticoids during inflammation.

Key Words: neutrophils, glucocorticoid insensitivity, glucocorticoid receptor, interleukin 8, inflammation


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