scholarly journals Effects of Rexinoids on Thyrotrope Function and the Hypothalamic-Pituitary-Thyroid Axis

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1438-1451 ◽  
Author(s):  
Vibha Sharma ◽  
William R. Hays ◽  
William M. Wood ◽  
Umarani Pugazhenthi ◽  
Donald L. St. Germain ◽  
...  
Keyword(s):  
Direct Effect ◽  
Promoter Activity ◽  
Retinoic Acid Receptor ◽  
Mrna Levels ◽  
Central Hypothyroidism ◽  
Iodothyronine Deiodinase ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis

Retinoid X receptor (RXR)-selective retinoids (rexinoids) can cause central hypothyroidism in humans, and this effect has been confirmed in rodent models. In this report, we characterized the effect of rexinoids on the hypothalamic-pituitary-thyroid axis in mice and TSH regulation in a thyrotrope-derived cell line. The synthetic rexinoid (LG 268) suppressed TSH and T4 levels in mice. Hypothalamic TRH mRNA was unaffected, but steady-state pituitary TSHβ mRNA levels were significantly lowered, suggesting a direct effect of rexinoids on thyrotropes. LG 268 suppressed TSH protein secretion and TSHβ mRNA in TαT1 thyrotropes as early as 8 h after treatment, whereas the retinoic acid receptor-selective retinoid (TTNPB) had no effect. Type 2 iodothyronine deiodinase (D2) mRNA and activity were suppressed by LG 268 in TαT1 cells, whereas only D2 mRNA was suppressed in mouse pituitaries. LG 268 suppressed TSHβ promoter activity by 42% and the −200 to −149 region accounted for a majority of the LG 268-mediated suppression of promoter activity. The RXRγ isotype is expressed in thyrotropes. In vitro transfection and in vivo transgenic studies indicate that any RXR isotype can mediate TSH suppression by rexinoids, but the RXRγ isotype is most efficient at mediating this response. RXRγ-deficient mice lacked pituitary D2 mRNA suppression by LG 268, but D2 activity remained intact. In summary, RXR-selective retinoids (rexinoids) have multiple effects on the hypothalamic-pituitary-thyroid axis. Rexinoids directly suppress TSH secretion, TSHβ mRNA levels and promoter activity, and D2 mRNA levels but have no direct effect on hypothalamic TRH levels. Rexinoids also stimulate type 1 iodothyronine deiodinase activity in the liver and pituitary.

scholarly journals Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in Vivo and in Vitro

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5525-5531 ◽  
Author(s):  
Gary M. Leong ◽  
Sofia Moverare ◽  
Jesena Brce ◽  
Nathan Doyle ◽  
Klara Sjögren ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Hepatoma Cells ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Wild Type ◽  
Hepatic Expression ◽  
Suppressors Of Cytokine Signaling

Abstract Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-α, ERβ, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERβ knockout mice but not in those lacking ERα or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P < 0.05) in constructs containing a region between nucleotides −1862 and −855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERα, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.

scholarly journals The role of leptin in the regulation of TSH secretion in the fed state: in vivo and in vitro studies

2002 ◽  
Vol 174 (1) ◽  
pp. 121-125 ◽  
Author(s):  
TM Ortiga-Carvalho ◽  
KJ Oliveira ◽  
BA Soares ◽  
CC Pazos-Moura
Keyword(s):  
Fold Increase ◽  
Adult Rats ◽  
Fed State ◽  
Rat Pituitary ◽  
Pituitary Thyroid Axis ◽  
Tsh Secretion ◽  
Thyroid Axis

Leptin has been shown to stimulate the hypothalamus-pituitary-thyroid axis in fasting rodents; however, its role in thyroid axis regulation under physiological conditions is still under investigation. Here it was investigated in freely fed rats whether leptin modulates thyrotroph function in vivo and whether leptin has direct pituitary effects on TSH release. Since leptin is produced in the pituitary, the possibility was also investigated that leptin may be a local regulator of TSH release. TSH was measured by specific RIA. Freely fed adult rats 2 h after being injected with a single s.c. injection of 8 microg leptin/100 g body weight showed a 2-fold increase in serum TSH (P<0.05). Hemi-pituitary explants incubated with 10(-9) and 10(-7) M leptin for 2 h showed a reduced TSH release of 40 and 50% respectively (P<0.05). Conversely, incubation of hemi-pituitary explants with antiserum against leptin, aiming to block the action of locally produced leptin, resulted in higher TSH release (45%, P<0.05). In conclusion, also in the fed state, leptin has an acute stimulatory effect on TSH release in vivo, acting probably at the hypothalamus. However, the direct pituitary effect of leptin is inhibitory and data also provide evidence that in the rat pituitary leptin may act as an autocrine/paracrine inhibitor of TSH release.

scholarly journals Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

2007 ◽  
Vol 18 (8) ◽  
pp. 2864-2872 ◽  
Author(s):  
Kelly J. Perkins ◽  
Utpal Basu ◽  
Murat T. Budak ◽  
Caroline Ketterer ◽  
Santhosh M. Baby ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Molecular Mechanisms ◽  
Neuromuscular Junctions ◽  
Protein Product ◽  
Mrna Levels ◽  
Laser Capture Microscopy ◽  
Erk Phosphorylation ◽  
Duchenne's Muscular Dystrophy

Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated extracellular signal-regulated kinase (ERK)-phosphorylation, leading to binding of GABPα/β to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extrasynaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extrasynaptic utrophin-A in muscle. Gel shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-box/EBS site. ERF overexpression repressed utrophin-A promoter activity; conversely, small interfering RNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extrasynaptic transcriptomes and gene transfer studies provide spatial and direct evidence, respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest “repressing repressors” as a potential strategy for achieving utrophin up-regulation in DMD, and they provide a model for utrophin-A regulation in muscle.

scholarly journals Cold Exposure Increases the Biosynthesis and Proteolytic Processing of Prothyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus via β-Adrenoreceptors

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4952-4964 ◽  
Author(s):  
Mario Perello ◽  
Ronald C. Stuart ◽  
Charles A. Vaslet ◽  
Eduardo A. Nillni
Keyword(s):  
Paraventricular Nucleus ◽  
Molecular Mechanisms ◽  
Protein Biosynthesis ◽  
Camp Response Element Binding ◽  
Proteolytic Processing ◽  
Hypothalamic Paraventricular Nucleus ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis

Different physiological conditions affect the biosynthesis and processing of hypophysiotropic proTRH in the hypothalamic paraventricular nucleus, and consequently the output of TRH. Early studies suggest that norepinephrine (NE) mediates the cold-induced activation of the hypothalamic-pituitary-thyroid axis at a central level. However, the specific role of NE on the biosynthesis and processing of proTRH has not been fully investigated. In this study, we found that NE affects gene transcription, protein biosynthesis, and secretion in TRH neurons in vitro; these changes were coupled with an up-regulation of prohormone convertase enzymes (PC) 1/3 and PC2. In vivo, NE is the main mediator of the cold-induced activation of the hypothalamic-pituitary-thyroid axis at the hypothalamic level, in which it potently stimulates the biosynthesis and proteolytic processing of proTRH through a coordinated up-regulation of the PCs. This activation occurs via β-adrenoreceptors and phosphorylated cAMP response element binding signaling. In contrast, α-adrenoreceptors regulate TRH secretion but not proTRH biosynthesis and processing. Therefore, this study provides novel information on the molecular mechanisms of control of hypophysiotropic TRH biosynthesis.

scholarly journals Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

2019 ◽  
Author(s):  
Kamila Kwiecien ◽  
Piotr Brzoza ◽  
Pawel Majewski ◽  
Izabella Skulimowska ◽  
Kamil Bednarczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Phase ◽  
Molecular Mechanisms ◽  
Retinoic Acid Receptor ◽  
Constitutive Expression ◽  
Sequencing Analysis ◽  
Mrna Levels ◽  
Pleiotropic Actions

AbstractChemerin is a chemoattractant protein with adipokine properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. It has gained more attention over the past few years due to its multilevel impact on metabolism and immune responses. The pleiotropic actions of chemerin include chemotaxis of dendritic cells, macrophages and natural killers (NK) subsets, bactericidal activity as well as regulation of adipogenesis and glucose metabolism. Therefore, reflecting the pleiotropic actions of chemerin, expression of RARRES2 is regulated by a variety of inflammatory and metabolic mediators. However, for most cell types, the molecular mechanisms controlling constitutive and regulated chemerin expression are poorly characterized. Here we show that RARRES2 mRNA levels in murine adipocytes are upregulated in vitro and in vivo by acute-phase cytokines, IL-1β and OSM. In contrast to adipocytes, these cytokines exerted a weak, if any, response in mouse hepatocytes, suggesting that the effect of IL-1β and OSM on chemerin expression is specific to fat tissue. Moreover, we show that DNA methylation controls the constitutive expression of chemerin. Bisulfite sequencing analysis showed low methylation levels within −735 to +258 bp of the murine RARRES2 gene promoter in unstimulated adipocytes and hepatocytes. In contrast to these cells, the RARRES2 promoter is highly methylated in B lymphocytes, cells that do not produce chemerin. Together, our findings reveal previously uncharacterized mediators and mechanisms controlling chemerin expression in various cells.

scholarly journals Lactobacillus acidophilus stimulates the expression of SLC26A3 via a transcriptional mechanism

2010 ◽  
Vol 298 (3) ◽  
pp. G395-G401 ◽  
Author(s):  
Geetu Raheja ◽  
Varsha Singh ◽  
Ke Ma ◽  
Redouane Boumendjel ◽  
Alip Borthakur ◽  
...  
Keyword(s):  
Western Blot ◽  
Lactobacillus Acidophilus ◽  
Promoter Activity ◽  
In Vivo Studies ◽  
Mrna Levels ◽  
Long Term Effects ◽  
Exchange Activity

Clinical efficacy of probiotics in treating various forms of diarrhea has been clearly established. However, mechanisms underlying antidiarrheal effects of probiotics are not completely defined. Diarrhea is caused either by decreased absorption or increased secretion of electrolytes and solutes in the intestine. In this regard, the electroneutral absorption of two major electrolytes, Na+ and Cl−, occurs mainly through the coupled operation of Na+/H+ exchangers and Cl−/OH− exchangers. Previous studies from our laboratory have shown that Lactobacillus acidophilus (LA) acutely stimulated Cl−/OH− exchange activity via an increase in the surface levels of the apical anion exchanger SLC26A3 (DRA). However, whether probiotics influence SLC26A3 expression and promoter activity has not been examined. The present studies were, therefore, undertaken to investigate the long-term effects of LA on SLC26A3 expression and promoter activity. Treatment of Caco-2 cells with LA for 6–24 h resulted in a significant increase in Cl−/OH− exchange activity. DRA mRNA levels were also significantly elevated in response to LA treatment starting as early as 8 h. Additionally, the promoter activity of DRA was increased by more than twofold following 8 h LA treatment of Caco-2 cells. Similar to the in vitro studies, in vivo studies using mice gavaged with LA also showed significantly increased DRA mRNA (∼4-fold) and protein expression in the colonic regions as assessed by Western blot analysis and immunofluorescence. In conclusion, increase in DRA promoter activity and expression may contribute to the upregulation of intestinal electrolyte absorption and might underlie the potential antidiarrheal effects of LA.

scholarly journals In Vivo Interaction of Steroid Receptor Coactivator (SRC)-1 and the Activation Function-2 Domain of the Thyroid Hormone Receptor (TR) β in TRβ E457A Knock-In and SRC-1 Knockout mice

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3927-3934 ◽  
Author(s):  
Manuela Alonso ◽  
Charles Goodwin ◽  
XiaoHui Liao ◽  
Tania Ortiga-Carvalho ◽  
Danielle S. Machado ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Steroid Receptor ◽  
Activation Function ◽  
Steroid Receptor Coactivator ◽  
Pituitary Thyroid Axis ◽  
Serum T4 ◽  
Thyroid Axis

The activation function-2 (AF-2) domain of the thyroid hormone (TH) receptor (TR)-β is a TH-dependent binding site for nuclear coactivators (NCoA), which modulate TH-dependent gene transcription. In contrast, the putative AF-1 domain is a TH-independent region interacting with NCoA. We determined the specificity of the AF-2 domain and NCoA interaction by evaluating thyroid function in mice with combined disruption of the AF-2 domain in TRβ, due to a point mutation (E457A), and deletion of one of the NCoAs, steroid receptor coactivator (SRC)-1. The E457A mutation was chosen because it abolishes NCoA recruitment in vitro while preserving normal TH binding and corepressor interactions resulting in resistance to TH. At baseline, disruption of SRC-1 in the homozygous knock-in (TRβE457A/E457A) mice worsened the degree of resistance to TH, resulting in increased serum T4 and TSH. During TH deprivation, disruption of AF-2 and SRC-1 resulted in a TSH rise 50% of what was seen when AF-2 alone was removed, suggesting that SRC-1 was interacting outside of the AF-2 domain. Therefore, 1) during TH deprivation, SRC-1 is necessary for activating the hypothalamic-pituitary-thyroid axis; 2) ligand-dependent repression of TSH requires an intact AF-2; and 3) SRC-1 may interact with the another region of the TRβ or the TRα to regulate TH action in the pituitary. This report demonstrates the dual interaction of NCoA in vivo: the TH-independent up-regulation possibly through another domain and TH-dependent down-regulation through the AF-2 domain.

scholarly journals Calcineurin activates interleukin-6 transcription in mouse skeletal muscle in vivo and in C2C12 myotubes in vitro

2010 ◽  
Vol 298 (1) ◽  
pp. R198-R210 ◽  
Author(s):  
David L. Allen ◽  
Jill J. Uyenishi ◽  
Allison S. Cleary ◽  
Ryan S. Mehan ◽  
Sarah F. Lindsay ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Exercise ◽  
Binding Sites ◽  
Promoter Activity ◽  
Wheel Running ◽  
Mrna Levels ◽  
Dna Binding Sites ◽  
Single Bout

Expression of the cytokine interleukin-6 (IL-6) by skeletal muscle is hugely increased in response to a single bout of endurance exercise, and this appears to be mediated by increases in intracellular calcium. We examined the effects of endurance exercise on IL-6 mRNA levels and promoter activity in skeletal muscle in vivo, and the role of the calcium-activated calcineurin signaling pathway on muscle IL-6 expression in vivo and in vitro. IL-6 mRNA levels in the mouse tibialis anterior (TA) were increased 2–10-fold by a single bout of treadmill exercise or by 3 days of voluntary wheel running. Moreover, an IL-6 promoter-driven luciferase transgene was activated in TA by both treadmill and wheel-running exercise and by injection with a calcineurin plasmid. Exercise also increased muscle mRNA expression of the calcineurin regulatory gene MCIP1, as did treatment of C2C12 myotubes with the calcium ionophore A23187. Cotransfection of C2C12 myotubes with a constitutively active calcineurin construct significantly increased while cotransfection with the calcineurin inhibitor CAIN inhibited activity of a mouse IL-6 promoter-reporter construct. Cotransfection with a myocyte enhancer-factor-2 (MEF-2) expression construct increased basal IL-6 promoter activity and augmented the effects of calcineurin cotransfection, while cotransfection with the MEF-2 antagonist MITR repressed calcineurin-activated IL-6 promoter activity in vitro. Surprisingly, cotransfection with a dominant-negative form of another calcineurin-activated transcription factor, nuclear factor activator of T cells (NFAT), greatly potentiated both basal and calcineurin-stimulated IL-6 promoter activity in C2C12 myotubes. Mutation of the MEF-2 DNA binding sites attenuated, while mutation of the NFAT DNA binding sites potentiated basal and calcineurin-activated IL-6 promoter activity. Finally, CREB and C/EBP were necessary for basal IL-6 promoter activity and sufficient to increase IL-6 promoter activity but had minimal roles in calcineurin-activated IL-6 promoter activity. Together, these results suggest that IL-6 transcription in skeletal muscle cells can be activated by a calcineurin-MEF-2 axis which is antagonized by NFAT.

Effect of vitamin A on the hypothalamo-pituitary-thyroid axis

1980 ◽  
Vol 238 (2) ◽  
pp. E174-E179 ◽  
Author(s):  
J. E. Morley ◽  
S. Melmed ◽  
A. Reed ◽  
B. G. Kasson ◽  
S. R. Levin ◽  
...  
Keyword(s):  
Vitamin A ◽  
Thyroid Stimulating Hormone ◽  
Hormone Response ◽  
Multiple Parameters ◽  
Thyroid Uptake ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Peripheral Clearance

This study reports the effects of the administration of pharmacologic doses of vitamin A on multiple parameters of thyroid function. Vitamin A decreased total T4 and T3 levels. With vitamin A treatment, there was a marked increase in the percentage dialyzable T3 and T4 both in vivo and in vitro. The serum-free T3 and T4 levels as measured by dialysis were on the whole normal in vitamin A-treated rats. Following thyroidectomy, the total T4 levels were still decreased, suggesting that vitamin A produced its effects by increasing peripheral clearance of thyroxine. Vitamin A did not alter basal thyroid stimulating hormone (TSH) or its response to thyroid releasing hormone, suggesting a relatively normal hypothalamic-pituitary-thyroid axis in vitamin A-treated animals. Vitamin A may decrease tissue responsiveness to thyroid hormones as evidenced by the tendency to decreased Na-K-ATPase activity in the livers from vitamin A-treated rats and the decreased growth hormone response to T3 in GH3 pituitary cultures as shown in this study and by the decreased basal metabolic rate found after vitamin A in previous studies. Vitamin A decreased thyroid gland size and increases 125I thyroid uptake. In vitro, vitamin A enhanced T4 to T3 conversion in hepatic homogenates.

Superoxide, Xanthine Oxidase and Platelet Reactions: Further Studies on Mechanisms by which Oxidants Influence Platelets

1981 ◽  
Vol 45 (03) ◽  
pp. 290-293 ◽  
Author(s):  
Peter H Levine ◽  
Danielle G Sladdin ◽  
Norman I Krinsky
Keyword(s):  
Superoxide Dismutase ◽  
Cytochrome C ◽  
Xanthine Oxidase ◽  
Direct Effect ◽  
Platelet Function ◽  
Experimental Conditions ◽  
Release Reaction

SummaryIn the course of studying the effects on platelets of the oxidant species superoxide (O- 2), Of was generated by the interaction of xanthine oxidase plus xanthine. Surprisingly, gel-filtered platelets, when exposed to xanthine oxidase in the absence of xanthine substrate, were found to generate superoxide (O- 2), as determined by the reduction of added cytochrome c and by the inhibition of this reduction in the presence of superoxide dismutase.In addition to generating Of, the xanthine oxidase-treated platelets display both aggregation and evidence of the release reaction. This xanthine oxidase induced aggreagtion is not inhibited by the addition of either superoxide dismutase or cytochrome c, suggesting that it is due to either a further metabolite of O- 2, or that O- 2 itself exerts no important direct effect on platelet function under these experimental conditions. The ability of Of to modulate platelet reactions in vivo or in vitro remains in doubt, and xanthine oxidase is an unsuitable source of O- 2 in platelet studies because of its own effects on platelets.

Sign in / Sign up

Export Citation Format

Share Document