# Role of regulatory T cell glucocorticoid-induced leucine zipper (GILZ) in the chronically inflamed intestine

> **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $120,750

## Abstract

Project Summary/Abstract
Glucocorticoid-induced leucine zipper (GILZ) is a broadly-expressed transcription factor whose expression is
induced via endogenous or synthetic glucocorticoid (GC) signaling through the glucocorticoid receptor (GR).
GILZ is thought to meditate many of GCs’ anti-inflammatory effects in T lymphocytes, such as induction of TGFβ
signaling and inhibition of NFκB, MAPK, and AP-1 pathways. Conditional deletion of GILZ in CD4+ T cells leads
to enhancement of experimental dinitrobenzene sulfonic acid (DNBS)-induced colitis, a Th1-mediated form of
experimental inflammatory bowel disease (IBD). Steroid hormones, including corticosteroids and sex steroid
hormones such as 17β-estradiol (estrogen, E2), demonstrate considerable promiscuity in receptor binding. E2
has been shown to antagonize GILZ in human uterine epithelial cells, but little is known regarding the
mechanism(s) by which it may contribute to GILZ expression and/or function in T cells. Our preliminary data
reveal a robust induction of GILZ at the mRNA and protein levels in regulatory T cells (Tregs) isolated from
Crohn’s disease (CD) patients and SAMP/YitFC (“SAMP”) mice, a spontaneous model of Crohn’s-like disease.
GILZ upregulation (“GILZhigh”) in these Tregs was associated with a relative decrease in estrogen receptor beta
(ERβ) expression, suggesting that GILZ expression in Tregs may be responsive to estrogen signaling.
Furthermore, GILZhigh Tregs exhibited reduced suppressive function compared to their GILZlow counterparts,
suggesting that optimal GILZ-mediated immunosuppression in Tregs may require intact ERβ signaling.
Several chronic inflammatory and autoimmune diseases exhibit reductions in ERβ expression and/or activity,
leading to the intriguing possibility that diminished ERβ expression contributes to inflammation via disruption of
normally-protective Treg GILZ-mediated mechanisms. Our hypothesis is that the protective functions of Treg-
specific GILZ require intact ERβ signaling, and therefore fail to mediated sufficient immunoprotection in
ERβ-depleted environments, such as the IBD intestine. The goal of this project is to determine the
mechanism(s) by which reduced ERβ-specific signaling influences the expression and function of GILZ in IBD-
associated Tregs. We will make use of novel tools (GILZ transgenic and knockout mice and MaxCyte lentiviral
transfection of primary human and murine T cells) to manipulate GILZ expression in ERβ-deficient versus –
sufficient Tregs in order to understand how intact ERβ signaling influences the expression (Subaim 1a) and
function (Subaim 1b) of Treg-specific GILZ. Leveraging a large cohort of CD patients available through the
Cleveland Digestive Disease Research Core Center (DDRCC), we will apply single-cell RNA sequencing to CD
patient mucosal Tregs (discarded surgical samples) in order to identify unique transcriptional signatures
(Subaim 1c) associated with ERβlow/GILZhigh Tregs. These assays will provide critical data...

## Key facts

- **NIH application ID:** 10057684
- **Project number:** 1R03DK123579-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Wendy Ann Goodman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $120,750
- **Award type:** 1
- **Project period:** 2020-07-13 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057684

## Citation

> US National Institutes of Health, RePORTER application 10057684, Role of regulatory T cell glucocorticoid-induced leucine zipper (GILZ) in the chronically inflamed intestine (1R03DK123579-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10057684. Licensed CC0.

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