Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function Aranda Clemente, Carlos José Arredondo-Amador, María Ocón, Borja Lavín, José Luis Aransay, Ana María Martínez Augustín, María Olga Sánchez De Medina López-Huertas, Fermín Mucosal barrier function Epithelial homeostasis Mucus production This work was supported by funds from the Ministry of Economy and Competitivity, partly with Fondo Europeo de Desarrollo Regional (FEDER) funds (BFU2014-57736-P, AGL2014-58883-R, SAF2017-88457-R, and AGL2017-85270-R), and by Junta de Andalucía (CTS235 and CTS164). B.O., C.J.A., and M.A.-A. were supported by fellowships from the Ministry of Education. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by Instituto de Salud Carlos III. Center for Cooperative Research in Biosciences (CIC bioGUNE) support was provided by the Basque Department of Industry, Tourism, and Trade (Etortek and Elkartek Programs), the Innovation Technology Department of Bizkaia County, CIBERehd Network, and Spanish Ministry of Economy and Competitiveness (MINECO) Severo Ochoa Excellence Accreditation (SEV-2016-0644). The authors have received funds and/or support from Amino Up Chemical, Pfizer, Hospira, Sanofi, Biosearch Life, Bioiberica and APC Europe. Glucocorticoids (GC) are important hormones involved in the regulation of multiple physiological functions. GC are also widely used antiinflammatory/immunosuppresant drugs. GC are synthesized by the adrenal cortex as part of the hypothalamus-pituitary-adrenal axis, and also by intestinal epithelial cells, among other peripheral sites. GC are one of the main therapy choices for the exacerbations of inflammatory bowel disease, but they are not useful to prolong remission, and development of tolerance with secondary treatment failure is frequent. Thus GC actions at the intestinal epithelial level are of great importance, both physiologically and pharmacologically. We generated a tamoxifen inducible NR3C1IEC model to study the effects of GC on epithelial cells in vivo. Nr3c1 deletion in epithelial cells of the small intestine and colon was associated with limited colonic inflammation at 1 week postdeletion, involving augmented epithelial proliferation and mucus production, plus local and systemic immune/inflammatory changes. This phenotype regressed substantially, but not completely, after 2 weeks. The mechanism may involve augmented inflammatory signaling by epithelial cells and/or defective barrier function. We conclude that the epithelial GC receptor plays a significant role in colonic homeostasis in basal conditions, but its deficiency can be compensated in the short term. Future studies are required to assess the impact of Nr3c1 deletion in other conditions such as experimental colitis. 2026-02-09T07:46:35Z 2026-02-09T07:46:35Z 2019 journal article Published version: Aranda, Carlos José et al. Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function. The FASEB Journal, 26 October 2019. https://doi.org/10.1096/fj.201900404RR https://hdl.handle.net/10481/110740 10.1096/fj.201900404RR eng open access Wiley