Paracrine glucocorticoid activity produced by mouse thymic epithelial cells

Pazirandeh, Ahmad; Xue, Yan; Rafter, Ingalill; Sjövall, Jan; Jondal, Mikael; Okret, Sam

doi:10.1096/fasebj.13.8.893

Cited by 111 publications

(85 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HEK 293T cells were transiently transfected with a GC receptor response element luciferase reporter construct and a GC receptor expression plasmid, as described elsewhere (Pazirandeh et al, 1999). Incubation with increasing concentrations of cortisol led to a dose-dependent induction of the reporter construct, that is, the GC receptor-dependent induction of luciferase activity.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Colon cancer cells produce immunoregulatory glucocorticoids

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The reporter plasmid GRE2tk and the expression plasmid for GC receptor SVGR1 were kindly provided by Sam Okret (Karolinska Institute, Stockholm, Sweden; Pazirandeh et al, 1999). The expression plasmids for human LRH-1 was kindly provided by Kristina Schoonjans (Ecole Polytechnique Federale de Lausanne EPFL, Lausanne, Switzerland).…”

Section: Plasmidsmentioning

confidence: 99%

Colon cancer cells produce immunoregulatory glucocorticoids

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Conversely, removal of endogenous GC by adrenalectomy leads to hypertrophy of the thymus [18] and spleen [19]. In addition to the adrenals, we and others have identified the thymus as a site of GC production [20][21][22][23]. A physiological role of GC in T cell development and selection is implied by the observation that TCR and glucocorticoid receptor (GR) signaling demonstrate crosstalk.…”

Section: Introductionmentioning

confidence: 99%

TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development

et al. 2005

View full text Add to dashboard Cite

“…Depletion of androgens through castration of animals results in thymic enlargement; consequently, androgen replacement reverses these effects (Olsen et al, 1991). Tissue-specific metabolism of hormones might impact organ function (Pazirandeh et al, 1999), but little is known about expression and function of steroid-metabolizing enzymes in the thymus. It is, however, well established that cytochrome P450 (P450s 1 ) monooxygenases play a major role in the metabolism of steroids (Simpson, 1997;Capdevila et al, 2000;Borlak, 2000a, 2002).…”

mentioning

confidence: 99%

Androgen Metabolism in Thymus of Fetal and Adult Rats

Borlak

Schulte²,

Thum³

2004

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Cytochrome P450 (P450) monooxygenases play a role in target tissue metabolic activation of xenobiotics and/or endogenous compounds, such as vasoactive molecules or hormones. Indeed, tissue-specific metabolism of steroids is important in a variety of organs, including thymus, and may alter tissue-specific functions. Steroids have been shown to regulate thymus growth and function, but surprisingly little is known about expression of the responsible enzyme systems in thymus tissue, nor is the thymus-specific biotransformation of testosterone known. We therefore investigated gene and protein expression, total protein content, and enzyme activity of major P450 isoforms and other key steroid-metabolizing enzymes in thymus tissue of adult and fetal rats. We detected 6␤-hydroxytestosterone (HT), 7␣-HT, 16␣-HT, 2␣-HT, and androstenedione to be major testosterone metabolites in the adult thymus. The high production of 7␣-HT and 16␣-HT correlated well with the gene and protein expression of CYP2A1/2 and CYP2B1/2 in thymus of adult animals. When compared with fetal thymic tissue, CYP2A1/2, 17␤-hydroxysteroid dehydrogenase isoform 1 (17␤-HSDH1) and the androgen receptor were 8-, 3-, and 3-fold more highly expressed in adult rats, whereas 17␤-HSDH2, 17␤-HSDH3, and 5␣-reductase were reduced to 12%, 0%, and 32% of those in fetal thymus. In conclusion, we demonstrated that rat thymus expresses a variety of cytochrome P450 monooxygenases and other steroid-metabolizing enzymes, and it successfully metabolizes testosterone. Changes of the underlying steroid-metabolizing enzyme systems may aid in understanding the role of androgens in altering biological functions of the thymus.

show abstract

Paracrine glucocorticoid activity produced by mouse thymic epithelial cells

Cited by 111 publications

References 44 publications

Colon cancer cells produce immunoregulatory glucocorticoids

Colon cancer cells produce immunoregulatory glucocorticoids

TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development

Androgen Metabolism in Thymus of Fetal and Adult Rats

Contact Info

Product

Resources

About