Intestinal Epithelial Cells Synthesize Glucocorticoids and Regulate T Cell Activation

Cima, Igor; Corazza, Nadia; Dick, Bernhard; Fuhrer, Andrea; Herren, Simon; Jakob, Sabine; Ayuni, Erick; Mueller, Christoph; Brunner, Thomas

doi:10.1084/jem.20031958

Cited by 174 publications

(247 citation statements)

References 45 publications

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“…Upon injection of anti-CD3 antibody, LRH-1, CYP11A1, and CYP11B1 become highly induced (23). Because TNBS or DSS treatment does not increase LRH-1 mRNA levels ( Fig.…”

Section: Conditional Deletion Of Lrh-1 In the Intestinal Epithelium Cmentioning

confidence: 99%

“…LRH-1 and the steroidogenic enzymes CYP11A1 and CYP11B1 are both expressed in the crypt region of the intestinal epithelial layer (15,23). Upon injection of anti-CD3 antibody, LRH-1, CYP11A1, and CYP11B1 become highly induced (23).…”

Section: Conditional Deletion Of Lrh-1 In the Intestinal Epithelium Cmentioning

confidence: 99%

“…Corticosterone synthesis in the intestinal mucosa of TNBS-challenged mice was assessed as described (23). Twenty-four hours after the induction of TNBS colitis, mice were killed and colons were isolated, washed, and cultured for 6 h in the absence or presence of 200 g/ml metyrapone, an agent blocking the activity of the corticosterol-synthesizing enzymes P450C11 and 11␤-HSD1.…”

Section: Measurement Of Intestinal Corticosterone Synthesismentioning

confidence: 99%

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LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Coste

Dubuquoy

Barnouin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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139

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Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocytedependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.Crohn's disease ͉ inflammation ͉ nuclear receptors ͉ steroidogenesis ͉ ulcerative colitis

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“…Upon injection of anti-CD3 antibody, LRH-1, CYP11A1, and CYP11B1 become highly induced (23). Because TNBS or DSS treatment does not increase LRH-1 mRNA levels ( Fig.…”

Section: Conditional Deletion Of Lrh-1 In the Intestinal Epithelium Cmentioning

confidence: 99%

Section: Conditional Deletion Of Lrh-1 In the Intestinal Epithelium Cmentioning

confidence: 99%

Section: Measurement Of Intestinal Corticosterone Synthesismentioning

confidence: 99%

See 1 more Smart Citation

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Coste

Dubuquoy

Barnouin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

139

205

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show abstract

“…However, different reports indicate that GC synthesis is not restricted to the adrenal glands but may also occur at other sites of the body (Noti et al, 2009), for example, the thymus (Vacchio et al, 1994), the brain (MacKenzie et al, 2000;Davies and MacKenzie, 2003) and the vascular endothelium (Takeda et al, 1994). Recently, we have characterized the intestinal epithelium as a major source of immunoregulatory GC (Cima et al, 2004;Mueller et al, 2006Mueller et al, , 2007Atanasov et al, 2008). In mice, intestinal GC synthesis is highly regulated and is induced upon activation of immune cells.…”

Section: Introductionmentioning

confidence: 99%

Colon cancer cells produce immunoregulatory glucocorticoids

et al. 2011

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Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. Initially thought to be exclusively produced by the adrenal glands, there is now increasing evidence for extra-adrenal sources of GCs. We have previously shown that the intestinal epithelium produces immunoregulatory GCs and that intestinal steroidogenesis is regulated by the nuclear receptor liver receptor homolog-1 (LRH-1). As LRH-1 has been implicated in the development of colon cancer, we here investigated whether LRH-1 regulates GC synthesis in colorectal tumors and whether tumor-produced GCs suppress T-cell activation. Colorectal cancer cell lines and primary tumors were found to express steroidogenic enzymes and regulatory factors required for the de novo synthesis of cortisol. Both cell lines and primary tumors constitutively produced readily detectable levels of cortisol, as measured by radioimmunoassay, thin-layer chromatography and bioassay. Whereas overexpression of LRH-1 significantly increased the expression of steroidogenic enzymes and the synthesis of cortisol, downregulation or inhibition of LRH-1 effectively suppressed these processes, indicating an important role of LRH-1 in colorectal tumor GC synthesis. An immunoregulatory role of tumor-derived GCs could be further confirmed by demonstrating a suppression of T-cell activation. This study describes for the first time cortisol synthesis in a non-endocrine tumor in humans, and suggests that the synthesis of bioactive GCs in colon cancer cells may account as a novel mechanism of tumor immune escape.

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“…Glucocorticoid drugs are immunosuppressive agents widely used to treat inflammatory disorders, including IBD (Barnes, 1998), but are also endogenously produced in the intestine where they are an important component of homeostasis (Cima et al, 2004;Mueller et al, 2006). The mechanism of glucocorticoids is attributed to pleiotropic effects of the glucocorticoid receptor (GR) on multiple transcriptional pathways.…”

Section: Endoplasmic Reticulum (Er) Stress In Intestinal Secretory Cementioning

confidence: 99%

Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins

Das¹,

Png²,

Oancea³

et al. 2013

J Cell Biol

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Intestinal Epithelial Cells Synthesize Glucocorticoids and Regulate T Cell Activation

Cited by 174 publications

References 45 publications

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Colon cancer cells produce immunoregulatory glucocorticoids

Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins

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