Covalent affinity labeling, radioautography, and immunocytochemistry localize the glucocorticoid receptor in rat testicular leydig cells

Stalker, Alison; Hermo, Louis; Antakly, Tony

doi:10.1002/aja.1001860406

Cited by 73 publications

(40 citation statements)

References 35 publications

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“…Sertoli cells, which produce IL-1 constitutively, do not appear to produce IL-1 , but rat and human Leydig cells express IL-1 in response to inflammatory stimulation in vitro (Lin et al 1993, Cudicini et al 1997, Jonsson et al 1999. It is possible that, even though the Leydig cells possess glucocorticoid receptors ( Stalker et al 1989), the production of IL-1 by these cells may not be responsive to glucocorticoid control due to differences in the regulatory regions of the IL-1 gene, for example. Alternatively, the different effects of DEX on IL-1 mRNA in the testis and liver might be explained by differential access of DEX to the two organs.…”

Section: Discussionmentioning

confidence: 98%

“…Glucocorticoids exert a negative feedback effect on the inflammatory response by reducing the production, secretion and actions of the principal inflammatory mediators, such as IL-1 , and are widely used clinically as anti-inflammatory agents (Kapcala et al 1995). However, glucocorticoids also inhibit testicular steroidogenesis by actions at the hypothalamus and pituitary (Bambino & Hsueh 1981), and by direct inhibition of P450scc, 3 -hydroxysteroid dehydrogenase and P450c17 levels (Sapolsky 1985, Hales & Payne 1989, Monder et al 1994, Gao et al 1996, acting through specific receptors on the Leydig cells (Stalker et al 1989). Glucocorticoid levels are elevated for 4-6 h following LPS treatment in humans and experimental animals (Wolff 1973, Stenzel-Poore et al 1993.…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of dexamethasone treatment on lipopolysaccharide-induced testicular inflammation and reproductive hormone inhibition in adult rats

Gow¹,

O'Bryan²,

Canny³

et al. 2001

Journal of Endocrinology

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A single intraperitoneal injection of lipopolysaccharide (LPS) causes a biphasic suppression of testicular steroidogenesis in adult rats, with inhibition at 6 h and 18-24 h after injection. The inhibition of steroidogenesis is independent of the reduction in circulating LH that also occurs after LPS treatment, indicating a direct effect of inflammation at the Leydig cell level. The relative contributions to this inhibition by intratesticular versus systemic responses to inflammation, including the adrenal glucocorticoids, was investigated in this study.Adult male Wistar rats (eight/group) received injections of LPS (0·1 mg/kg i.p.), dexamethasone (DEX; 50 µg/kg i.p.), LPS and DEX, or saline only (controls), and were killed 6 h, 18 h and 72 h later. Treatment with LPS stimulated body temperature and serum corticosterone levels measured 6 h later. Administration of DEX had no effect on body temperature, but suppressed serum corticosterone levels. At the dose used in this study, DEX alone had no effect on serum LH or testosterone at any time-point. Expression of mRNA for interleukin-1 (IL-1 ), the principal inflammatory cytokine, was increased in both testis and liver of LPS-treated rats. Serum LH and testosterone levels were considerably reduced at 6 h and 18 h after LPS treatment, and had not completely recovered by 72 h. At 6 h after injection, DEX inhibited basal IL-1 expression and the LPS-induced increase of IL-1 mRNA levels in the liver, but had no effect on IL-1 in the testis. The effects of DEX on IL-1 levels in the liver were no longer evident by 18 h. In LPS-treated rats, DEX caused a significant reversal of the inhibition of serum LH and testosterone at 18 h, although not at 6 h or 72 h. Accordingly, DEX inhibited the systemic inflammatory response, but had no direct effect on either testicular steroidogenesis or intra-testicular inflammation, at the dose employed.These data suggest that the inhibition of Leydig cell steroidogenesis at 6 h after LPS injection, which was not prevented by co-administration of DEX, is most likely due to direct actions of LPS at the testicular level. In contrast, the later Leydig cell inhibition (at 18 h) may be attributable to extra-testicular effects of LPS, such as increased circulating inflammatory mediators or the release of endogenous glucocorticoids, that were inhibited by DEX treatment. These data indicate that the early and late phases of Leydig cell inhibition following LPS administration are due to separate mechanisms.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Differential effects of dexamethasone treatment on lipopolysaccharide-induced testicular inflammation and reproductive hormone inhibition in adult rats

Gow¹,

O'Bryan²,

Canny³

et al. 2001

Journal of Endocrinology

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“…Apparently, the classic GRs are involved in these glucocorticoid actions. Leydig cells express classic GRs [19][20][21]. The Leydig cell responds to glucocorticoids.…”

Section: Stress and Leydig Cell Functionmentioning

confidence: 99%

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Lian

Lin

et al. 2008

Steroids

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Stress-mediated elevations in circulating glucocorticoid levels lead to corresponding rapid declines in testosterone production by Leydig cells in the testis. In previous studies we have established that glucocorticoids act on Leydig cells directly, through the classic glucocorticoid receptor (GR), and that access to the GR is controlled prior to the GR by a metabolizing pathway mediated by the type 1 isoform of 11β-hydroxysteroid dehydrogenase (11βHSD1). This enzyme is bidirectional (with both oxidase and reductase activities) and in the rat testis is exclusively localized in Leydig cells where it is abundantly expressed and may catalyze the oxidative inactivation of glucocorticoids. The predominant reductase direction of 11βHSD1 activity in liver cells is determined by an enzyme, hexose-6-phosphate dehydrogenase (H6PDH), on the luminal side of the smooth endoplasmic reticulum (SER). Generation of the pyridine nucleotide cofactor NADPH by H6PDH stimulates the reductase direction of 11βHSD1 resulting in increased levels of active glucocorticoids in liver cells. Unlike liver cells, steroidogenic enzymes including 17β-hydroxysteroid dehydrogenase 3 (17βHSD3) forms the coupling with 11βHSD1. Thus the physiological concentrations of androstenedione serve as a substrate for 17βHSD3 utilizing NADPH to generate NADP+, which drives 11βHSD1 in Leydig cells primarily as an oxidase; thus eliminating the adverse effects of glucocorticoids on testosterone production. At the same time 11βHSD1 generates NADPH which promotes testosterone biosynthesis by stimulating 17βHSD3 in a cooperative cycle. This enzymatic coupling constitutes a rapid mechanism for modulating glucocorticoid control of testosterone biosynthesis. Under stress conditions, glucocorticoids also have rapid actions to suppress cAMP formation thus to lower testosterone production.

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“…Leydig cells express the Gc receptor (GR,NR3C1) and are the main targets of Gc action in the testis (Evain et al 1976, Stalker et al 1989, Schwarzenbach et al 2003. Although the molecular mechanisms by which Gc decrease steroidogenesis have not been entirely defined, numerous studies have shown that Gc can inhibit expression of enzymes involved in testosterone biosynthesis such as Star, Cyp11a1, Cyp17a1, Hsd3b and Hsd17b3 (Hales & Payne 1989, Payne & Sha 1991, Wang et al 2000, Huang & Shirley 2001, Schwarzenbach et al 2003, Badrinarayanan et al 2006, Fon & Li 2007.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

Martin¹,

Tremblay

2008

Journal of Molecular Endocrinology

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It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain the mechanism of action of Gc on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory (STAR) protein, have been shown to be repressed by Gc in a GR-dependent manner but the underlying mechanisms remain to be fully elucidated. Here, we found that dexamethasone (Dex), a potent synthetic Gc, partly antagonizes the cAMP-dependent stimulation of the mouse Star promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at K95 bp previously implicated in the activation of the Star promoter by the nuclear receptors, NR4A1 and NR5A1. Dex was found to inhibit NR4A1-dependent transactivation of the Star promoter in Leydig cells by decreasing NR4A1, but not NR5A1, recruitment to the proximal Star promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that Dex did not affect NR4A1 or NR5A1 expression in response to cAMP. These data suggest that NR4A1 would be associated with the GR in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.

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Covalent affinity labeling, radioautography, and immunocytochemistry localize the glucocorticoid receptor in rat testicular leydig cells

Cited by 73 publications

References 35 publications

Differential effects of dexamethasone treatment on lipopolysaccharide-induced testicular inflammation and reproductive hormone inhibition in adult rats

Differential effects of dexamethasone treatment on lipopolysaccharide-induced testicular inflammation and reproductive hormone inhibition in adult rats

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1

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