Ultradian cortisol pulsatility encodes a distinct, biologically important signal.
BACKGROUND
Cortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored.


OBJECTIVE
Determination of the biological consequences of ultradian cortisol pulsatility.


METHODS
A novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured.


RESULTS
Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer(211)).


CONCLUSIONS
Cortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function.
Endocrine Sciences Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
Andrew
A
McMaster
Maryam
M
Jangani
Paula
P
Sommer
Namshik
N
Han
Andy
A
Brass
Stephen
S
Beesley
Weiqun
W
Lu
Andrew
A
Berry
Andrew
A
Loudon
Rachelle
R
Donn
David W
DW
Ray
D000204:Activity Cycles / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D049109:Cell Proliferation; D002470:Cell Survival; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D006854:Hydrocortisone / Q000502:physiology*; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D011965:Receptors, Glucocorticoid; D006854:Hydrocortisone
Novartis Found Symp. 2000;227:244-57; discussion 257-60
10752074
Metabolism. 1998 Feb;47(2):143-8
9472960
Nat Rev Genet. 2001 Jun;2(6):418-27
11389458
J Neuroendocrinol. 2001 Oct;13(10):905-11
11679059
Bioinformatics. 2006 Nov 15;22(22):2775-81
16966362
Front Neuroendocrinol. 2004 Jul;25(2):69-76
15571755
Nucl Recept Signal. 2006;4:e009
16741567
Am J Physiol. 1989 Jul;257(1 Pt 1):E6-14
2750897
J Virol. 2002 Mar;76(5):2168-79
11836394
Nat Cell Biol. 2009 Sep;11(9):1093-102
19684579
Chromosome Res. 2006;14(1):107-16
16506100
Arch Physiol Biochem. 2002 Apr;110(1-2):90-3
11935404
Eur J Pharmacol. 2008 Apr 7;583(2-3):255-62
18339373
Mol Biol Cell. 2008 Aug;19(8):3308-22
18508913
Nat Protoc. 2009;4(1):44-57
19131956
J Clin Endocrinol Metab. 1993 Jun;76(6):1505-10
8501158
Rheum Dis Clin North Am. 2005 Feb;31(1):xiii-xvi
15639051
PLoS Genet. 2007 Jun;3(6):e94
17559307
Nature. 2008 Mar 6;452(7183):112-5
18322535
Endocrinology. 1998 Oct;139(10):4044-52
9751481
Endocrinology. 1998 Feb;139(2):443-50
9449609
N Engl J Med. 2005 Oct 20;353(16):1711-23
16236742
Mol Cell. 2008 Mar 14;29(5):611-24
18342607
Rheum Dis Clin North Am. 2005 Feb;31(1):115-29, ix-x
15639059
Mol Cell Biol. 2004 Apr;24(7):2682-97
15024059
J Clin Invest. 1997 Jun 15;99(12):2923-9
9185516
J Clin Endocrinol Metab. 1995 Jan;80(1):54-9
7829639
Nature. 2008 Mar 6;452(7183):45-50
18322525
J Clin Endocrinol Metab. 1990 Aug;71(2):452-63
2166071
Genes Dev. 2005 May 1;19(9):1116-27
15879558
Ann N Y Acad Sci. 2004 Jun;1024:213-20
15265783
Endocrinology. 1998 Feb;139(2):437-40
9449607
J Clin Endocrinol Metab. 2000 Jun;85(6):2203-14
10852453
FASEB J. 2007 Feb;21(2):402-14
17185747
Mol Endocrinol. 2008 Jun;22(6):1320-30
18308897
Genome Res. 2009 Dec;19(12):2163-71
19801529
Oncogene. 2007 Nov 1;26(50):7111-21
17496926
Nature. 2005 Mar 17;434(7031):338-45
15735639