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J Wigren
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S Surapureddi
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AG Olsson
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CK Glass
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S Hammarstrom
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M Soderstrom
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Peroxisome proliferator-activated receptor gamma (PPARgamma) colocalizes with oxidized low-density lipoprotein (LDL) in foam cells in atherosclerotic lesions. We have explored a potential role of oxidized fatty acids in LDL as PPARgamma activators. LDL from patients suffering from intermittent claudication due to atherosclerosis was analyzed using HPLC and gas chromatography/mass spectrophotometry and found to contain 9-hydroxy and 13-hydroxyoctadecadienoic acid (9- and 13-HODE), as well as 5-hydroxy-, 12-hydroxy- and 15-hydroxyeicosatetraenoic acid (5-, 12- and 15-HETE respectively). PPARgamma was potently activated by 13(S)-HODE and 15(S)-HETE, as judged by transient transfection assays in macrophages or CV-1 cells. 5(S)- and 12(S)-HETE as well as 15-deoxy-Delta(12,14)-prostaglandin J(2) also activated PPARgamma but were less potent. Interestingly, the effect of the lipoxygenase products 13(S)-HODE and 15(S)-HETE as well as of the drug rosiglitazone were preferentially enhanced by the coactivator CREB-binding protein, whereas the effect of the cyclooxygenase product 15-deoxy-Delta(12,14)-prostaglandin J(2) was preferentially enhanced by steroid receptor coactivator-1. We interpret these results, which may have relevance to the pathogenesis of atherosclerosis, to indicate that the lipoxygenase products on the one hand and the cyclooxygenase product on the other exert specific effects on the transcription of target genes through differential coactivator recruitment by PPARgamma/9-cis retinoic acid receptor heterodimer complexes.

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J. R. WALL
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P. TWOHIG
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B. CHARTIER
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A possible effect of thyroid hormones on numbers of mononuclear cells and immune reactivity has been studied in hyperthyroid and hypothyroid guinea-pigs and rats. There were no major changes in populations of blood mononuclear cells in hyperthyroid or hypothyroid animals compared with populations in euthyroid animals. Although there was some evidence for depressed cell-mediated responses to an extract of Candida (monilia) albicans in hyperthyroid rats as assessed by skin tests, this was minor, and responses in tuberculin purified protein derivative (PPD) were normal in all groups, whilst production of macrophage migration inhibition factor in response to PPD and Candida was similar in the three groups of animals. Antibody responses to sheep red blood cells, a thymic-dependent antigen, tended to be depressed in hyperthyroid and hypothyroid rats and increased in hyperthyroid and hypothyroid guinea-pigs, although this was significant only for hyperthyroid guinea-pigs 16 days after immunization. Responses to trinitrophenol-Ficoll, a thymic-independent antigen, were similar to the three groups of guinea-pigs. Thus, a major effect of excess or deficiency of thyroid hormone on immune responses to foreign antigens has not been demonstrated, although it is possible that immune reactions against thyroid antigens may be more sensitive to the effect of thyroid hormones than responses to foreign antigens.

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P Delerive
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JC Fruchart
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B Staels
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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARalpha is highly expressed in liver, skeletal muscle, kidney, heart and the vascular wall. PPARgamma is predominantly detected in adipose tissue, intestine and macrophages. PPARs are activated by fatty-acid derivatives and pharmacological agents such as fibrates and glitazones which are specific for PPARalpha and PPARgamma respectively. PPARs regulate lipid and lipoprotein metabolism, glucose homeostasis, cell proliferation and differentiation, and apoptosis. PPARalpha controls intra- and extracellular lipid metabolisms whereas PPARgamma triggers adipocyte differentiation and promotes lipid storage. In addition, PPARs also modulate the inflammatory response. PPAR activators have been shown to exert anti-inflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases and acute-phase proteins. PPARs negatively regulate the transcription of inflammatory response genes by antagonizing the AP-1, nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription and nuclear factor of activated T-cells signalling pathways and by stimulating the catabolism of proinflammatory eicosanoids. These recent findings indicate a modulatory role for PPARs in inflammation with potential therapeutical applications in chronic inflammatory diseases.

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G Aust
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M Steinert
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C Boltze
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S Kiessling
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C Simchen
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Thyroid glands affected by Graves' disease (GD) show striking leukocytic infiltration, mainly by T-cells. The mechanisms by which the various leukocytes are maintained in the thyroid are unknown. Growth-regulated oncogene-alpha (GRO-alpha) in interaction with its receptor CXCR2 is a chemoattractant for both T-cells and neutrophils and may be one of the chemokines involved in the cell maintenance. GRO-alpha and CD18 mRNA as a marker of leukocytic infiltration were quantified in thyroid tissue using competitive RT-PCR. We found very high GRO-alpha mRNA levels in all thyroid tissues. In GD patients (n=16), the GRO-alpha mRNA did not correlate with the CD18 mRNA level or thyroid peroxidase and TSH-receptor antibodies in patients' sera. In thyroid autonomy (n=10), the GRO-alpha mRNA levels were significantly lower in autonomous single adenomas compared with the corresponding normal tissue. In order to define the cellular source of GRO-alpha mRNA and protein, we examined various thyroid-derived cells. Thyrocytes, thyroid-derived leukocytes and fibroblasts showed basal GRO-alpha mRNA and protein expression, which was remarkably upregulated by different stimuli in vitro. The expression of GRO-alpha by thyroid carcinoma cell lines confirms that thyrocytes may actually produce GRO-alpha. As shown by flow cytometry and immunohistology, CD68+ monocytes/macrophages are the only cell population strongly expressing CXCR2 in the thyroid.

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L. E. Valladares
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A. M. Ronco
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A. M. Pino
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ABSTRACT

The trophic action of LH on Leydig cells involves the triggering of a number of cellular events including changes in protein synthesis. This latter change has led a number of workers to postulate an effect of LH on RNA synthesis. A direct action of LH on RNA synthesis, however, has been difficult to assess.

The aim of the present work was to analyse the effect of LH on RNA synthesis in vitro during sexual development. Studies were performed using purified Leydig cells from rats of 20, 30, 40, 50, 60 and 90 days of age. The results obtained show that basal uridine incorporation into RNA increases in an age-dependent manner in rats from 20 to 60 days of age and then remains unchanged until 90 days of age. A stimulatory effect of LH on RNA synthesis was clearly demonstrated only in the youngest rats (20 and 30 days old). In order to differentiate the effect of LH on different RNA populations, the RNA synthesized by immature and mature rats was analysed using a poly(U)-Sepharose column. In 20-day-old rats, LH stimulated both unbound and poly(A) RNA, although a more marked effect was clearly demonstrated on the latter. On the other hand, LH had an identical effect on both unbound and poly(A) RNA obtained from Leydig cells of 60-day-old rats.

This stimulatory effect of LH on RNA synthesis in Leydig cells from immature rats seemed specific, since effectors which act on interstitial cells, such as LH-releasing hormone, [Arg8]-vasopressin and FSH (which may act on macrophages) did not modify RNA synthesis. It is concluded that LH stimulates RNA synthesis in rat Leydig cells and that this effect is expressed differentially according to sexual maturity.

J. Endocr. (1986) 110, 551–556

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C E Bryant
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A Tomlinson
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J A Mitchell
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C Thiemermann
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D A Willoughby
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Abstract

Nitric oxide produced from l-arginine by nitric oxide synthase (NOS) acts in a variety of biological processes via the stimulation of guanylyl cyclase and subsequent elevation of cGMP. Constitutive, calcium-dependent isoforms of NOS are found in endothelial cells (eNOS) and neurones (nNOS), while macrophages express an inducible, calcium-independent isoform (iNOS) in response to the action of certain cytokines or bacterial endotoxin. While the regulation of NOS by exogenous glucocorticoids and steroid hormones is well documented, the effects of endogenous steroid hormones on NOS activity, such as those released during the oestrous cycle, is unknown. Here we demonstrate, using specific antibodies for eNOS, nNOS and iNOS, the presence of NOS in the epithelium of rat fallopian tubes at pro-oestrus, late pro-oestrus, oestrus, metoestrus and dioestrus. Western blot analysis of rat fallopian tube homogenates revealed a protein band at approximately 125 kDa which was recognised by antibodies to different isoforms of NOS, but no bands at the expected molecular weights (eNOS, 140 kDa; nNOS, 160 kDa; iNOS, 135 kDa). NOS activity in fallopian tubes was measured by the conversion of l-[3H]arginine to l-[3H]citrulline. Both calcium-dependent and -independent NOS activities were present. However, in late pro-oestrus when circulating oestrogens are low, NOS activity was reduced in comparison to all other stages of the oestrous cycle. Thus we show that NOS is present in the epithelial lining of the fallopian tube and is recognised at a previously undescribed molecular weight. The changes in NOS activity in these cells during the oestrous cycle may modulate tube motility and contribute to sucessful fertility.

Journal of Endocrinology (1995) 146, 149–157

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KATHLEEN HALL
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H. SALIMI KHALIGH
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SUMMARY

Glycogen, and activities of amylophosphorylase, transglycosylase, uridine diphosphate glucose-glycogen glucosyl transferase (glycogen synthetase) and alkaline phosphatase were investigated by histochemical techniques in uteri of 44 spayed hamsters, untreated and injected with oestrogen (Oe) or progesterone (P) alone or in combination, and with or without relaxin (R). Chemical determinations of glycogen content were made for some uteri.

Glycogen was visualized only in myometrial and arterial muscle fibres and migrating leucocytes. Almost none was revealed by histochemical techniques in uteri of controls and after P although chemical determinations showed moderate amounts present; this is discussed. Oe and Oe + R increased glycogen in muscle fibres of the longitudinal layer and less consistently of the circular layer. Oe + P and Oe + P + R produced greater increase in the longitudinal but no increase in the circular layers. Phosphorylase activity was visualized in myometrial and arterial muscle fibres only. Controls showed greatest activity in the circular muscle fibres. Progesterone alone produced a slight increase in the longitudinal layer. All other treatments produced strong activity in the fibres of the longitudinal layer but less consistent increase in those of the circular layer. The techniques did not differentiate between the active and the inactive forms of the enzyme and this is discussed in relation to hormonal action.

The distribution of transglycosylase appeared to be similar to that of phosphorylase.

Preliminary tests of glycogen synthetase revealed activity in fibres of the longitudinal layer and (in two animals given Oe) the circular layer.

In untreated controls and after Oe and Oe + R, alkaline phosphatase activity was confined to epithelia, vascular endothelium and some macrophages. Activity also appeared in stromal cells and in fibroblasts of myometrial connective tissue after P, Oe + P and Oe + P + R. Myometrial muscle fibres showed no activity before or after any of the treatments.

With the combinations and doses used, no certain effect of relaxin was recorded.

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L. I. AGUADO
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G. S. ALVIAL
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E. M. RODRÍGUEZ
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Two hypophysial partes distales were grafted under the kidney capsule of intact female rats. The plasma prolactin levels 15, 45 and 90 days after the operation were determined. At the same postoperative intervals the grafted glands of some of the operated rats were processed for conventional light and electron microscopy and for the demonstration of prolactin, FSH and LH according to the unlabelled immunoperoxidase procedure. The ultrastructural characteristics of the transplanted secretory cells and the amount and distribution of the immunoreactive material within their cytoplasm were used to evaluate approximately the secretory activity of these cells.

Although levels of prolactin in the three experimental groups were significantly higher than those in control rats, a decrease in prolactin level was detected in 71% of the samples taken 45 days after operation. At day 15 the graft was completely surrounded by lymphoid cells whereas at day 45 these cells had invaded the whole graft. In the group sampled at day 90 the graft was free of lymphoid cells. When traced immunocytochemically the three types of cells followed different patterns of evolution after transplantation. Most prolactotrophs were hypertrophied in all groups but, in addition, they underwent a process leading to hyperplasia some time between days 45 and 90 after operation. Syncytial formations which probably correspond to multinucleated prolactotrophs were present only in the group sampled at day 90. The number of LH and FSH cells had decreased in the group at day 45 and by day 90 the former remained scarce but immunoreactive FSH cells were no longer found. At the ultrastructural level clear signs of involution of gonadotrophs and degradation by macrophages were seen in the graft 45 days after operation.

The relation between the morphology and hormone content of the graft and hormone content of the plasma is discussed, together with several questions raised by the results. Pituitary transplantation can be used as an experimental model only if the time-dependent changes described here are taken into account.

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A. P. Weetman
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S. Cohen
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M. W. Makgoba
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L. K. Borysiewicz
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ABSTRACT

Intercellular adhesion molecule-1 (ICAM-1), hitherto identified on activated B cells, macrophages, dendritic cells, endothelia and certain epithelial cells, serves as a ligand for the lymphocyte function-associated antigen-1 (LFA-1). ICAM-1 binding by LFA-1 enhances the efficiency of lymphocyte-target cell and lymphocyte-accessory cell interactions. We have investigated the in-vitro expression of ICAM-1 by cultured thyroid cells from five patients with Graves' disease using indirect immunofluorescence analysis, and found that 30 ± 11% (mean ± s.d.) of cells were ICAM-1 positive under basal conditions. The proportion of cells which were ICAM-1 positive and the amount of ICAM-1 per cell (assessed by fluorescence intensity) were both increased in all cases by the cytokines γ-interferon, interleukin-1 and tumour necrosis factor. Immunohistochemical analysis of frozen sections from thyroidectomy specimens demonstrated ICAM-1 on thyroid follicular cells in areas of lymphocytic infiltration in patients with Graves' disease (n = 2) or Hashimoto's thyroiditis (n = 2). ICAM-1 was not found in specimens from a patient with a toxic multinodular goitre or a patient with Graves' disease without focal lymphocytic accumulation. These results suggest that the thyroid epithelium may express ICAM-1 as well as major histocompatibility complex class II antigens, such as HLA-DR, in response to locally synthesized cytokines. The enhanced expression of ICAM-1 may render these cells more susceptible as targets for lymphocytemediated cytotoxicity, and together with HLA-DR antigen expression may increase the accessory cell capability of the thyroid follicular cells.

Journal of Endocrinology (1989) 122, 185–191

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M Holstad
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S Sandler
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In earlier studies it has been shown that prolactin (PRL) is a stimulating factor for the immune system, and it has been suggested that PRL might antagonize immunosuppressive effects of glucocorticoids. PRL has been reported to affect the cytokine secretion pattern, by elevating cytokine gene expression in macrophages, after the onset of sepsis. It also promotes the antibody response in mice where it increases the production of interferon-gamma (IFN-gamma) and inhibits interleukin-1 (IL-1) production. Due to these properties, PRL might influence the development of autoimmune type 1 diabetes. The aim of the present study was to examine the effects of two drugs; PRL and bromocriptine (BC) in vivo on the development of hyperglycemia and pancreatic insulitis in mice treated with multiple doses of streptozotocin (STZ) (40 mg/kg body weight, i.p.). The dopaminergic agonist BC is known to inhibit PRL secretion. In another set of experiments, the direct effects of PRL on the function of pancreatic islets exposed to STZ in vitro were studied. Mice treated with STZ became gradually hyperglycemic, and concomitant treatment with PRL (4 mg/kg body weight) for 21 days significantly reduced the elevation in blood glucose levels from day 10 onwards (P<0.05). Morphologic examinations of the pancreas on day 21 of mice receiving STZ injections revealed a marked insulitis, but only moderate insulitis in the STZ treated animals given PRL. BC administration (10 mg/kg body weight) in combination with STZ did not significantly affect the elevation in blood glucose levels or the insulitis. PRL or BC administration alone did not change the serum glucose concentration. This study indicates that PRL may affect hyperglycemia in the early phase of autoimmune diabetes. We suggest that it might be due to counteraction of autoimmune immunologic mechanisms and/or enhancement of beta-cell regeneration.

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