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Sci Rep. 2017 Jul 3;7(1):4502. doi: 10.1038/s41598-017-04755-w.

Chronic stress and intestinal barrier dysfunction: Glucocorticoid receptor and transcription repressor HES1 regulate tight junction protein Claudin-1 promoter.

Author information

1
University of Michigan Medical School, Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, 48109, USA. zhenggen@umich.edu.
2
University of Michigan Medical School, Department of Computational Medicine and Bioinformatics, Ann Arbor, 48109, USA.
3
University of Michigan Medical School, Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, 48109, USA.
4
Beijing Friendship Hospital Affiliated to Capital Medical University, Department of Gastroenterology and Hepatology, Beijing, 100050, China.
5
University of Michigan Medical School, Department of Pathology, Ann Arbor, 48109, USA.
6
University of Michigan School of Public Health, Department of Environmental Health Sciences, Ann Arbor, 48109, USA.
7
Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Abstract

Chronic stress and elevated glucocorticoid hormone are associated with decreases in the intestinal epithelial tight junction protein claudin-1 (CLDN1). Human/rat CLDN1 promoters contain glucocorticoid response elements (GREs) and adjacent transcription repressor HES1 binding N-boxes. Notch signaling target HES1 expression was high and glucocorticoid receptor (NR3C1) low at the crypt base and the pattern reversed at the crypt apex. Chronic stress reduced overall rat colon HES1 and NR3C1 that was associated with CLDN1 downregulation. Chromatin-immunoprecipitation experiments showed that HES1 and NR3C1 bind to the CLDN1 promoter in rat colon crypts. The binding of NR3C1 but not HES1 to CLDN1 promoter significantly decreased in chronically stressed animals, which was prevented by the NR3C1 antagonist RU486. We employed the 21-day Caco-2/BBe cell model to replicate cell differentiation along the crypt axis. HES1 siRNA treatment early in differentiation increased CLDN1. In contrast, stress levels of cortisol decreased CLDN1 in late differentiation stage but not in the early stage. HES1 was high, whereas NR3C1 and CLDN1 were low in the early stage which reversed in the late stage, e.g. HES1/NR3C1 binding to CLDN1 promoter demonstrates a dynamic and reciprocal pattern. These results suggest that chronic stress impairs colon epithelium homeostasis and barrier function via different mechanisms along the crypt axis.

PMID:
28674421
PMCID:
PMC5495803
DOI:
10.1038/s41598-017-04755-w
[Indexed for MEDLINE]
Free PMC Article

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