scholarly journals Hypothalamic-Pituitary Cytokine Network

Endocrinology ◽  
2004 ◽  
Vol 145 (1) ◽  
pp. 104-112 ◽  
Author(s):  
Anastasia Kariagina ◽  
Dmitry Romanenko ◽  
Song-Guang Ren ◽  
Vera Chesnokova
Keyword(s):  
Hpa Axis ◽  
Knockout Mice ◽  
Single Gene ◽  
Pituitary Cells ◽  
Mrna Levels ◽  
Acth Secretion ◽  
Double Knockout ◽  
Cytokine Network ◽  
Human Pituitary

Abstract Cytokines expressed in the brain and involved in regulating the hypothalamus-pituitary-adrenal (HPA) axis contribute to the neuroendocrine interface. Leukemia inhibitory factor (LIF) and LIF receptors are expressed in human pituitary cells and murine hypothalamus and pituitary. LIF potently induces pituitary proopiomelanocortin (POMC) gene transcription and ACTH secretion and potentiates CRH induction of POMC. In vivo, LIF, along with CRH, enhances POMC expression and ACTH secretion in response to emotional and inflammatory stress. To further elucidate specific roles for both CRH and LIF in activating the inflammatory HPA response, double-knockout mice (CRH/LIFKO) were generated by breeding the null mutants for each respective single gene. Inflammation produced by ip injection of lipopolysaccharide (1 μg/mouse) to double CRH and LIF-deficient mice elicited pituitary POMC induction similar to wild type and markedly higher than in single null animals (P < 0.0.01). Double-knockout mice also demonstrated robust corticosterone response to inflammation. High pituitary POMC mRNA levels may reflect abundant TNFα, IL-1β, and IL-6 activation observed in the hypothalamus and pituitary of these animals. Our results suggest that increased central proinflammatory cytokine expression can compensate for the impaired HPA axis function and activates inflammatory ACTH and corticosterone responses in mice-deficient in both CRH and LIF.

scholarly journals Desensitization of the adrenocorticotrophin responses to arginine vasopressin and corticotrophin-releasing hormone in ovine anterior pituitary cells

2003 ◽  
Vol 178 (3) ◽  
pp. 491-501 ◽  
Author(s):  
A Hassan ◽  
S Chacko ◽  
D Mason
Keyword(s):  
Arginine Vasopressin ◽  
Anterior Pituitary ◽  
Prolonged Exposure ◽  
No Reduction ◽  
Pituitary Cells ◽  
Acth Secretion ◽  
Releasing Hormone ◽  
Anterior Pituitary Cells

Following repeated or prolonged exposure to either corticotrophin-releasing hormone (CRH) or arginine vasopressin (AVP), pituitary adrenocorticotrophin (ACTH) responsiveness is reduced. This study compared the characteristics of desensitization to CRH and AVP in perifused ovine anterior pituitary cells. Desensitization to AVP occurred at relatively low AVP concentrations and was both rapid and readily reversible. Treatment for 25 min with AVP at concentrations greater than 2 nM caused significant reductions in the response to a subsequent 5 min 100 nM AVP pulse (IC(50)=6.54 nM). Significant desensitization was observed following pretreatment with 5 nM AVP for as briefly as 5 min. Desensitization was greater following a 10 min pretreatment, but longer exposures caused no further increase. Resensitization was complete within 40 min following 15 min treatment with 10 nM AVP. Continuous perifusion with 0.01 nM CRH had no effect on AVP-induced desensitization. Treatment with 0.1 nM CRH for either 25 or 50 min caused no reduction in the response to a subsequent 5 min stimulation with 10 nM CRH. When the pretreatment concentration was increased to 1 nM significant desensitization was observed, with a greater reduction in response occurring after 50 min treatment. Recovery of responsiveness was progressive following 50 min treatment with 1 nM CRH and was complete after 100 min. Our data show that in the sheep AVP desensitization can occur at concentrations and durations of AVP exposure within the endogenous ranges. This suggests that desensitization may play a key role in regulating ACTH secretion in vivo. If, as has been suggested, CRH acts to set corticotroph gain while AVP is the main dynamic regulator, any change in responsiveness to CRH may significantly influence the overall control of ACTH secretion.

In vitro effects of ketoconazole on corticotrope cell morphology and ACTH secretion of two pituitary adenomas removed from patients with Nelson's syndrome

1989 ◽  
Vol 121 (2) ◽  
pp. 185-190 ◽  
Author(s):  
L.Jimenez Reina ◽  
A. Leal-Cerro ◽  
J. Garcia ◽  
P.P. Garcia-Luna ◽  
R. Astorga ◽  
...  
Keyword(s):  
Volume Density ◽  
Pituitary Cells ◽  
Acth Secretion ◽  
Nelson’S Syndrome ◽  
Human Pituitary ◽  
Human Pituitary Adenoma ◽  
Nelson's Syndrome ◽  
In Vitro Effects ◽  
Intracellular Changes

Abstract. The direct effects of ketoconazole on the secretion of ACTH by human pituitary adenoma cells from 2 patients with Nelson's syndrome were studied in vitro. Stereologically quantified, intracellular changes affect the surface density of the endoplasmic reticulum (it decreased by 73%), the volume density of the secretion granules (it decreased by 49%), and the volume density of lysosomes (it decreased by 67%). The hormone released in the culture medium decreased depending on the doses of ketoconazole used; 10 μmol/l decreased ACTH levels by 31%. These data show that ketoconazole induce marked changes on corticotrope morphology and ACTH secretion in pituitary cells obtained from patients with Nelson's syndrome.

Regulation of the epithelial Ca2+ channels in small intestine as studied by quantitative mRNA detection

2003 ◽  
Vol 285 (1) ◽  
pp. G78-G85 ◽  
Author(s):  
Monique van Abel ◽  
Joost G. J. Hoenderop ◽  
Annemiete W. C. M. van der Kemp ◽  
Johannes P. T. M. van Leeuwen ◽  
René J. M. Bindels
Keyword(s):  
Knockout Mice ◽  
Hormonal Regulation ◽  
Transport Proteins ◽  
Ovariectomized Rats ◽  
Mrna Levels ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Genes Encoding ◽  
Calbindin D

The epithelial Ca2+ channels TRPV5 and TRPV6 are localized to the brush border membrane of intestinal cells and constitute the postulated rate-limiting entry step of active Ca2+ absorption. The aim of the present study was to investigate the hormonal regulation of these channels. To this end, the effect of 17β-estradiol (17β-E2), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and dietary Ca2+ on the expression of the duodenal Ca2+ transport proteins was investigated in vivo and analyzed using realtime quantitative PCR. Supplementation with 17β-E2 increased duodenal gene expression of TRPV5 and TRPV6 but also calbindin-D9K and plasma membrane Ca2+-ATPase (PMCA1b) in ovariectomized rats. 25-Hydroxyvitamin D3-1α-hydroxylase (1α-OHase) knockout mice are characterized by hyperparathyroidism, rickets, hypocalcemia, and undetectable levels of 1,25(OH)2D3 and were used to study the 1,25(OH)2D3-dependency of the stimulatory effects of 17β-E2. Treatment with 17β-E2 upregulated mRNA levels of duodenal TRPV6 in these 1α-OHase knockout mice, which was accompanied by increased serum Ca2+ concentrations from 1.69 ± 0.10 to 2.03 ± 0.12 mM ( P < 0.05). In addition, high dietary Ca2+ intake normalized serum Ca2+ in these mice and upregulated expression of genes encoding the duodenal Ca2+ transport proteins except for PMCA1b. Supplementation with 1,25(OH)2D3 resulted in increased expression of TRPV6, calbindin-D9K, and PMCA1b and normalization of serum Ca2+. Expression levels of duodenal TRPV5 mRNA are below detection limits in these 1α-OHase knockout mice, but supplementation with 1,25(OH)2D3 upregulated the expression to significant levels. In conclusion, TRPV5 and TRPV6 are regulated by 17β-E2 and 1,25(OH)2D3, whereas dietary Ca2+ is positively involved in the regulation of TRPV6 only.

scholarly journals TAT-μUtrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice

2011 ◽  
Vol 111 (1) ◽  
pp. 200-205 ◽  
Author(s):  
Jarrod A. Call ◽  
James M. Ervasti ◽  
Dawn A. Lowe
Keyword(s):  
Knockout Mice ◽  
Skeletal Muscles ◽  
Ex Vivo ◽  
Eccentric Contraction ◽  
Mdx Mice ◽  
Double Knockout ◽  
Replacement Treatment ◽  
Generating Capacity

Previously, we demonstrated functional substitution of dystrophin by TAT-μUtrophin (TAT-μUtr) in dystrophin-deficient mdx mice. Herein, we addressed whether TAT-μUtr could improve the phenotype of dystrophin and utrophin double-knockout ( mdx:utr−/−) mice. Specifically, we quantitatively compared survival and quality of life assessments in mdx:utr−/− mice receiving TAT-μUtr protein administration against placebo-treated mdx:utr−/− mice (PBS). Additionally, skeletal muscles from TAT-μUtr and PBS mice were tested in vivo and ex vivo for strength and susceptibility to eccentric contraction-induced injury. We found the TAT-μUtr treatment extended life span 45% compared with mice administered PBS. This was attributed to significantly increased food consumption (3.1 vs. 1.8 g/24 h) due to improved ability to search for food as daily cage activities were greater in TAT-μUtr mice (e.g., 364 vs. 201 m ambulation/24 h). The extensor digitorum longus muscles of TAT-μUtr-treated double-knockout mice also displayed increased force-generating capacity ex vivo (8.3 vs. 6.4 N/cm2) and decreased susceptibility to injury ex vivo and in vivo. These data indicate that the functional benefits of TAT-μUtr replacement treatment extend to the mdx:utr−/− double-knockout mouse and support its development as a therapy to mitigate muscle weakness in patients with Duchenne muscular dystrophy.

scholarly journals Polyamine homeostasis in arginase knockout mice

2007 ◽  
Vol 293 (4) ◽  
pp. C1296-C1301 ◽  
Author(s):  
Joshua L. Deignan ◽  
Justin C. Livesay ◽  
Lisa M. Shantz ◽  
Anthony E. Pegg ◽  
William E. O'Brien ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Polyamine Metabolism ◽  
Mrna Levels ◽  
Ornithine Aminotransferase ◽  
Double Knockout ◽  
Mammalian Tissues ◽  
Knockout Animals ◽  
Regulatory Functions ◽  
Arginase I

The role of ornithine decarboxylase (ODC) in polyamine metabolism has long been established, but the exact source of ornithine has always been unclear. The arginase enzymes are capable of producing ornithine for the production of polyamines and may hold important regulatory functions in the maintenance of this pathway. Utilizing our unique set of arginase single and double knockout mice, we analyzed polyamine levels in the livers, brains, kidneys, and small intestines of the mice at 2 wk of age, the latest timepoint at which all of them are still alive, to determine whether tissue polyamine levels were altered in response to a disruption of arginase I (AI) and II (AII) enzymatic activity. Whereas putrescine was minimally increased in the liver and kidneys from the AII knockout mice, spermidine and spermine were maintained. ODC activity was not greatly altered in the knockout animals and did not correlate with the fluctuations in putrescine. mRNA levels of ornithine aminotransferase (OAT), antizyme 1 (AZ1), and spermidine/spermine- N1-acetyltransferase (SSAT) were also measured and only minor alterations were seen, most notably an increase in OAT expression seen in the liver of AI knockout and double knockout mice. It appears that putrescine catabolism may be affected in the liver when AI is disrupted and ornithine levels are highly reduced. These results suggest that endogenous arginase-derived ornithine may not directly contribute to polyamine homeostasis in mice. Alternate sources such as diet may provide sufficient polyamines for maintenance in mammalian tissues.

Differential activation of the pituitary-adrenocortical axis after stress in the rat: use of two genetically selected lines (Roman low- and high-avoidance rats) as a model

1989 ◽  
Vol 123 (3) ◽  
pp. 477-485 ◽  
Author(s):  
C.-D. Walker ◽  
R. W. Rivest ◽  
M. J. Meaney ◽  
M. L. Aubert
Keyword(s):  
Glucocorticoid Receptor ◽  
Conditioned Avoidance ◽  
Plasma Corticosterone ◽  
Type I ◽  
Pituitary Cells ◽  
Acth Secretion ◽  
Rapid Acquisition ◽  
Basal Plasma

ABSTRACT We have examined the activation of the pituitary-adrenal axis in two lines of rats, the Roman high (RHA)- and low (RLA)-avoidance rats known to be emotionally different. These rats are selected for rapid acquisition of a conditioned avoidance response (RHA) compared with failure to acquire this response (RLA). In this study the endocrine response (ACTH, corticosterone, aldosterone) of RLA and RHA rats to two types of stress was examined: exposure to openfield stress for 10 min (Op) or exposure to ether vapours for 3 min (E). Basal plasma ACTH concentrations were lower in RLA than in RHA rats (RLA: 110·8 ± 24·5 ng/l; RHA: 252·7 ± 60·8 ng/l, P<0·05) but the absolute values of ACTH reached after both types of stress were comparable between RLA and RHA rats. Plasma corticosterone and aldosterone under resting conditions were not different between RLA and RHA rats. Plasma corticosterone was higher in RLA following openfield stress (P<0·05) while no differences between RLA and RHA were observed after ether stress (RHA: basal = 66±14·nmol/l, Op =384± 55, E= 606± 75; RLA: basal=121±52, Op = 612 ±92, E= 698 ± 89). Stressinduced increases in plasma aldosterone were higher in the RLA line after both types of stress (RHA: basal = 175±36 pmol/l, Op = 546±53, E= 563± 47; RLA: basal = 272 ± 64, Op =1246 ± 91, E= 863 ± 72). Pituitary responsiveness to exogenous corticotrophinreleasing factor (CRF) in vivo and in vitro differed in the two lines: administration of ovine CRF (10 μg/kg body weight, i.p.) resulted in significant increases in ACTH secretion but the response was significantly lower in RHA rats (RHA: 511·1 ±41·5 ng/l; RLA: 831·4 ± 70·3 ng/l, P<0·01). Dispersed pituitary cells from the RHA line exhibited a smaller response to CRF (10 nmol/l) treatment in vitro compared with cells derived from the RLA rats (RHA: 750 ± 83% of control; RLA: 1374 ±79, P<0·01) suggesting differences in pituitary sensitivity to CRF between the two lines. Additional differences at the pituitary level were observed since the type II glucocorticoid receptor population in RHA rats was higher than in RLA rats (RHA: 246±13 fmol [3H]RU28362 bound/mg protein; RLA: 173±18, P<0·01). Similarly, hippocampal type I glucocorticoid receptor population was increased in RHA rats (RHA: 172·2 ± 8·3 fmol [3H]aldosterone bound/mg protein; RLA: 116·7±7·3, P< 0·01). It is concluded that first, differences in pituitary activity between RLA and RHA rats are distinct from changes observed at the adrenal level, secondly, increased stress-induced ACTH output in the RLA line is associated with enhanced pituitary sensitivity to CRF and possibly with diminished corticosterone inhibitory feedback action on CRF and ACTH secretion, and thirdly, the possible involvement of differences in the pattern of CRF secretion between RLA and RHA rats on resting pituitary ACTH secretion cannot be excluded. Journal of Endocrinology (1989) 123, 477–485

scholarly journals Curcumin acts as anti-tumorigenic and hormone-suppressive agent in murine and human pituitary tumour cells in vitro and in vivo

2009 ◽  
Vol 16 (4) ◽  
pp. 1339-1350 ◽  
Author(s):  
C Schaaf ◽  
B Shan ◽  
M Buchfelder ◽  
M Losa ◽  
J Kreutzer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Tumour Cell ◽  
Curcuma Longa ◽  
Pituitary Tumour ◽  
Pituitary Cells ◽  
Facs Analysis ◽  
Human Pituitary ◽  
Tumour Cell Lines

Curcumin (diferuloylmethane) is the active ingredient of the spice plant Curcuma longa and has been shown to act anti-tumorigenic in different types of tumours. Therefore, we have studied its effect in pituitary tumour cell lines and adenomas. Proliferation of lactosomatotroph GH3 and somatotroph MtT/S rat pituitary cells as well as of corticotroph AtT20 mouse pituitary cells was inhibited by curcumin in monolayer cell culture and in colony formation assay in soft agar. Fluorescence-activated cell sorting (FACS) analysis demonstrated curcumin-induced cell cycle arrest at G2/M. Analysis of cell cycle proteins by immunoblotting showed reduction in cyclin D1, cyclin-dependent kinase 4 and no change in p27kip. FACS analysis with Annexin V-FITC/7-aminoactinomycin D staining demonstrated curcumin-induced early apoptosis after 3, 6, 12 and 24 h treatment and nearly no necrosis. Induction of DNA fragmentation, reduction of Bcl-2 and enhancement of cleaved caspase-3 further confirmed induction of apoptosis by curcumin. Growth of GH3 tumours in athymic nude mice was suppressed by curcumin in vivo. In endocrine pituitary tumour cell lines, GH, ACTH and prolactin production were inhibited by curcumin. Studies in 25 human pituitary adenoma cell cultures have confirmed the anti-tumorigenic and hormone-suppressive effects of curcumin. Altogether, the results described in this report suggest this natural compound as a good candidate for therapeutic use on pituitary tumours.

scholarly journals Prolactin (PRL)-Releasing Peptide Stimulates PRL Secretion from Human Fetal Pituitary Cultures and Growth Hormone Release from Cultured Pituitary Adenomas1

2001 ◽  
Vol 86 (6) ◽  
pp. 2826-2830 ◽  
Author(s):  
Tami Rubinek ◽  
Moshe Hadani ◽  
Gad Barkai ◽  
Shlomo Melmed ◽  
Ilan Shimon
Keyword(s):  
Primary Cultures ◽  
Pituitary Hormones ◽  
Pituitary Cells ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Human Pituitary ◽  
Cell Adenoma ◽  
In Vitro Effects

The hypothalamic peptide PRL-releasing peptide (PrRP) has recently been cloned and identified as a ligand of an orphan pituitary receptor that stimulates in vitro PRL secretion. PrRP also induces PRL release in rats in vivo, especially in normal cycling females. However, no information on the effects of PrRP in the human is available. To elucidate the role of PrRP in regulating human anterior pituitary hormones, we used human PrRP-31 in primary cultures of human pituitary tissues, including fetal (20–27 weeks gestation) and normal adult pituitaries, as well as PRL- and GH-secreting adenomas. PrRP increased PRL secretion from human fetal pituitary cultures in a dose-dependent manner by up to 35% (maximal effect achieved with 10 nm), whereas TRH was slightly more potent for PRL release. Coincubation with estradiol resulted in enhanced fetal PRL response to PrRP, and GH release was only increased in the presence of estradiol. Although PRL secretion from PRL-cell adenomas was not affected by PrRP, PrRP induced PRL release from cultures of a GH-cell adenoma that cosecreted PRL. PrRP enhanced GH release in several GH-secreting adenomas studied by 25–27%, including GH stimulation in a mixed PRL-GH-cell tumor. These results show for the first time direct in vitro effects of PrRP-31 on human pituitary cells. PrRP is less potent than TRH in releasing PRL from human fetal lactotrophs and is unable to release PRL from PRL-cell adenomas in culture, but stimulated GH from several somatotroph adenomas. Thus, PrRP may participate in regulating GH, in addition to PRL, in the human pituitary.

scholarly journals Defects in Axonal Elongation and Neuronal Migration in Mice with Disrupted tau and map1b Genes

2000 ◽  
Vol 150 (5) ◽  
pp. 989-1000 ◽  
Author(s):  
Yosuke Takei ◽  
Junlin Teng ◽  
Akihiro Harada ◽  
Nobutaka Hirokawa
Keyword(s):  
Knockout Mice ◽  
Neuronal Migration ◽  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Double Knockout ◽  
Microtubule Organization ◽  
Axonal Elongation ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

Tau and MAP1B are the main members of neuronal microtubule-associated proteins (MAPs), the functions of which have remained obscure because of a putative functional redundancy (Harada, A., K. Oguchi, S. Okabe, J. Kuno, S. Terada, T. Ohshima, R. Sato-Yoshitake, Y. Takei, T. Noda, and N. Hirokawa. 1994. Nature. 369:488–491; Takei, Y., S. Kondo, A. Harada, S. Inomata, T. Noda, and N. Hirokawa. 1997. J. Cell Biol. 137:1615–1626). To unmask the role of these proteins, we generated double-knockout mice with disrupted tau and map1b genes and compared their phenotypes with those of single-knockout mice. In the analysis of mice with a genetic background of predominantly C57Bl/6J, a hypoplastic commissural axon tract and disorganized neuronal layering were observed in the brains of the tau+/+map1b−/− mice. These phenotypes are markedly more severe in tau−/−map1b−/− double mutants, indicating that tau and MAP1B act in a synergistic fashion. Primary cultures of hippocampal neurons from tau−/−map1b−/− mice showed inhibited axonal elongation. In these cells, a generation of new axons via bundling of microtubules at the neck of the growth cones appeared to be disturbed. Cultured cerebellar neurons from tau−/−map1b−/− mice showed delayed neuronal migration concomitant with suppressed neurite elongation. These findings indicate the cooperative functions of tau and MAP1B in vivo in axonal elongation and neuronal migration as regulators of microtubule organization.

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