UNIPROT:P01178 - FACTA Search

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Query: UNIPROT:P01178 (oxytocin)
15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thymic repertoire of neuroendocrine 'self' antigens has been previously described on the basis of the intrathymic expression of neurohypophysial (NHP)- and tachykinin-related peptide signals and receptors. According to that model, the cryptocrine signalling between thymic epithelial/nurse cells and thymocytes through NHP-related signals and receptors constitutes one accessory pathway in the process of T-cell differentiation and/or activation. A pharmacological manipulation of that novel type of cell-to-cell signalling was tested by the investigation of the immunomodulatory properties of novel cyclic hexapeptide oxytocin (OT) antagonists (MSD Research Laboratories). These compounds were found to significantly inhibit the productions of cytokines (mainly IL-1 beta and IL-6) elicited by anti-CD3 treatment of human whole blood cell cultures. Cytokine productions were more significantly reduced by OT antagonists in whole blood cell cultures derived from female volunteers than in those obtained from male donors, suggesting an influence of the gonadal steroid environment on the expression of NHP peptide receptors by immune cells. These observations support the concept of novel immunomodulating approaches through immune-specific neuropeptide antagonists, as well as the pharmacological value of such strategies in selective immunotherapy.
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PMID:Immunomodulatory properties of cyclic hexapeptide oxytocin antagonists. 149 61

Simultaneous microdialysis in the brain and blood was used to monitor the release of vasopressin and oxytocin within the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei and into the systemic circulation of urethane-anaesthetized male rats before and after central administration of interleukin-1 beta (IL-1 beta). Following intracerebroventricular infusion of the cytokine (200 ng/5 microliters), the content of vasopressin (up to 278% compared to vehicle-treated control, P < 0.01 compared to vehicle-treated control and preinfusion baseline) but not oxytocin (up to 148%, not significant) in 30-min blood microdialysates was found to be increased. This peripheral release was accompanied by a transient rise in vasopressin (up to 163%, P < 0.05) and oxytocin (up to 182%, P < 0.05) release within the SON, the peak typically occurring during the first and second 30-min collection intervals after IL-1 beta respectively. In contrast, in the simultaneously microdialysed PVN, both vasopressin and oxytocin failed to respond to intracerebroventricular IL-1 beta. In another series of experiments, IL-1 beta was directly infused (20 ng/0.5 microliters) into either the SON or PVN during microdialysis of the corresponding nucleus. The cytokine caused a significant and immediate rise in intra-SON release of both vasopressin (up to 225%, P < 0.01) and oxytocin (up to 178%, P < 0.05). Again, in the PVN, nonapeptide release, although tending to be stimulated in response to intranuclear IL-1 beta, failed to reach statistical significance. The cytokine-induced central and peripheral release pattern appeared to be independent of the rise in body temperature observed after IL-1 beta administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 beta stimulates both central and peripheral release of vasopressin and oxytocin in the rat. 762 Jun 10

The labour-inducing activity of RU486 (mifepristone) in different species including the human is relatively low in advanced stages of pregnancy. However, it increases myometrial responsiveness to prostaglandins and oxytocin and it also induces cervical ripening. The labour-inducing and labour-conditioning activities of various progesterone antagonists (antiprogestins) and the progesterone synthase inhibitor epostane were analysed at the pre-term period of pregnancy in various animal models. In guinea pigs and Tupaja belangeri (species showing no spontaneous progesterone withdrawal prior to parturition) onapristone, which is a 'pure' progesterone receptor antagonist, effectively induced parturition at pre-term but not during mid-pregnancy. On the other hand, antiprogestins showing mixed agonist/antagonist activities (e.g. RU486, lilopristone, ZK 112993) and epostane were only partially effective in inducing pre-term parturition in both species. In guinea pigs, all anti-progestins increased myometrial responsiveness to oxytocin and prostaglandins, onapristone being approximately 10 times more effective than RU486. This effect was seen at doses of antiprogestins which alone did not induce labour at all. The increase in oxytocin response in onapristone-primed guinea pigs was not accompanied by an increase in myometrial oxytocin receptors, although a marked increase in myometrial gap junctions occurred. Antiprogestins induced a pronounced cervical ripening in pregnant and non-pregnant guinea pigs and rats independently of the action of prostaglandins. The infiltration of polymorphonuclear granulocytes, macrophages and mast cells into the cervix after antiprogestin treatment indicates that cytokines or other chemotactic agents may mediate this effect. In guinea pigs in late pregnancy, the cytokines interleukin (IL)-8 and IL-1 beta induced a cervical ripening morphologically similar to the antiprogestin effect. Our data indicate that progesterone may control uterine quiescence by reducing myometrial responsiveness, i.e. by down-regulating gap junctions and inhibiting cervical maturation, but not by suppressing the release of endogenous uterine stimulants which may be controlled by other factors. Antiprogestins may be used to prepare the uterus for oxytocin- and prostaglandin-induction of labour without influencing uterine motor function. Onapristone may be a preferable antiprogestin as an adjunct to labour and delivery at term because it has high labour-conditioning potency, no progesterone-agonistic activity, short half-life and low antiglucocorticoid activity.
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PMID:The use of progesterone antagonists for cervical ripening and as an adjunct to labour and delivery. 796 60

The cytokine interleukin-6 (IL-6) is produced by a variety of cells, including macrophages, T-cells, and B-cells. Recent studies have confirmed a neuroendocrine role for IL-6 in the regulation of anterior pituitary (AP) hormone release. Because the neurointermediate pituitary lobe (NIL) may modulate AP hormone release, we investigated the production of IL-6 by NIL cells in vitro. NIL tissue removed from pituitary glands of male Long-Evans rats was enzymatically and mechanically dispersed, and the cells were subsequently cultured in 96-well tissue culture plates for 4-6 days in 10% serum-containing RPMI-1640. Test incubations were performed in serum-free RPMI-1640, and IL-6 concentrations were determined using the 7TD1 cell bioassay. Preliminary studies revealed a cell-dependent release of IL-6: increasing the number of NIL cells per well from 6.25 to 50 x 10(3) revealed detectable basal release of IL-6 between 25-50 x 10(3) cells/well. The endotoxin lipopolysaccharide (LPS; 100 ng/ml) and IL-1 beta (100 ng/ml) stimulated IL-6 release at 25 and 50 x 10(3) cells/well. Subsequent studies used a cell density of 50 x 10(3) cells/well and demonstrated time-dependent 3- to 6-fold inductions of IL-6 release by 100 ng/ml IL-1 beta and LPS. Concentration-response studies revealed maximal stimulation of IL-6 release by 1 ng/ml and a minimally effective concentration of 1 pg/ml for both IL-1 beta and LPS. Treatment of NIL cells with 1-10 mM (Bu)2cAMP increased IL-6 release by 7- to 14-fold. Endotoxin and IL-1 beta also enhanced the accumulation of IL-6 messenger RNA in these cells. Vasopressin and oxytocin (1 microM) inhibited LPS and IL-1 beta stimulation of IL-6 release from NIL cells, but did not inhibit IL-6 release from AP cells. Immunofluorescent dual labeling of NIL cells for flow cytometry revealed that greater than 95% of the cells did not stain for CD11b/c (common epitope found on monocytes, granulocytes, and macrophages) or CD45 (leukocyte common antigen). These results demonstrate for the first time the synthesis and release of IL-6 from cultured NIL cells. Agents that enhance IL-6 release [LPS, IL-1 beta, and (Bu)2cAMP] from other cell types also increase IL-6 release from NIL cells. Vasopressin and oxytocin inhibition of IL-6 release suggests a role for these neuropeptides in feedback inhibition in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurointermediate pituitary lobe cells synthesize and release interleukin-6 in vitro: effects of lipopolysaccharide and interleukin-1 beta. 803 2

Interleukin-1 (IL-1) and interleukin-6 (IL-6) have been reported to stimulate the release of corticotrophin-releasing hormone (CRH) in vitro, the response being antagonized by the cyclo-oxygenase inhibitor, indomethacin. The effects of cytokines on the other major ACTH-releasing hormone, vasopressin (AVP), and the other neurohypophysial hormone, oxytocin, have been little studied, and the published data are conflicting. We have therefore used a previously validated rat hypothalamic explant model to evaluate whether IL-1 beta and IL-6 can directly activate the AVP and oxytocin neurosecretory system. In addition, we have also investigated the effects of inhibition of cyclo-oxygenase (CO) and lipoxygenase (LO) activities on the stimulated release of AVP and oxytocin by means of a series of antagonists, including a specific LO pathway inhibitor. The static rat hypothalamic incubation system used involves fresh hypothalamic explants with consecutive 20-min incubations, and estimation of AVP and oxytocin concentrations in the medium by specific and sensitive radioimmunoassays. It was found that IL-1 beta produced a dose-dependent increase in the release of AVP and oxytocin at doses of 10 and 100 U/ml (P < 0.005). Only at the higher dose of 100 U/ml was IL-6 able to increase significantly AVP and oxytocin release (P < 0.05). These stimulatory effects of IL-1 beta and IL-6 were blocked by cyclo-oxygenase inhibitors, indomethacin (28 microM) and ibuprofen (100 nM), but not by the lipoxygenase inhibitor, BW A4C (10 micrograms/ml), suggesting that prostaglandins are involved in this process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-1 beta and interleukin-6 stimulate neurohypophysial hormone release in vitro. 804 16

Nitric oxide (NO) synthase (NOS), the enzyme responsible for NO formation, is found in hypothalamic neurons containing oxytocin (OT), vasopressin (VP), and to a lesser extent corticotropin-releasing factor (CRF). Because NO is reported to modulate endocrine activity, we have investigated the hypothesis that endogenous NO participates in ACTH released by various secretagogues in the rat. In the adult male rat, the intravenous injection of interleukin-1 beta (IL-1 beta; 0.2-0.3 micrograms/kg), VP (0.3-0.9 micrograms/kg), and OT (30 micrograms/kg) significantly increased plasma ACTH and corticosterone levels. Pretreatment with the L-form, but not the D-form, of N omega nitro-L-arginine-methylester (L-NAME; a specific inhibitor of NOS) markedly augmented the effects of these secretagogues whether it was injected acutely or over a 4 d period. Blockade of NOS activity also caused significant (P < 0.01) extensions of the duration of action of IL-1 beta, VP, and OT. In contrast, L-NAME did not significantly alter the stimulatory action of peripherally injected CRF, or centrally administered IL-1 beta. Administration of L-arginine, but not D-arginine (100 mg/kg), used as a substrate for basal NO synthesis and which did not by itself alter the activity of the hypothalamic-pituitary-adrenal (HPA) axis, blunted IL-1-induced ACTH secretion, and reversed the interaction between L-NAME and IL-1 beta. The stimulatory action of endotoxin, a lipopolysaccharide that releases endogenous cytokines, was also augmented by inhibition of NO formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In the rat, endogenous nitric oxide modulates the response of the hypothalamic-pituitary-adrenal axis to interleukin-1 beta, vasopressin, and oxytocin. 815 53

The promoter regions of the rat corticotropin-releasing factor (CRF), oxytocin (OT), and vasopressin (AVP) genes contain sequences similar to the cis-acting response element identified for NGFI-B, an immediate-early gene structurally related to the steroid hormone receptor superfamily. Combined immuno- and hybridization histochemical approaches were used to determine whether challenges that influence the synthesis and secretion of CRF, OT, and/or AVP result in altered expression in neurosecretory neurons of NGFI-B and another immediate-early gene, c-fos, which is widely used as a marker for functionally activated neurons. NGFI-B mRNA was found to be expressed at constitutively high levels in the telencephalon, but not in the endocrine hypothalamus, of unperturbed controls; basal levels of c-fos expression were uniformly low throughout the CNS. NGFI-B and c-fos mRNAs, and Fos protein, were induced with a similar time course and in similar neuroendocrine cell types in response to acute hypotensive hemorrhage (15% reduction in blood volume), intravenous injection of interleukin-1 beta (IL-1 beta; 1.87 micrograms/kg), chronic salt loading (7 d maintenance on 2% saline), and acute bilateral adrenalectomy. c-fos mRNA and Fos protein were readily demonstrable in afferent pathways that have been implicated as mediating the neuroendocrine responses in the three stress paradigms; these include medullary catecholaminergic cell groups in response to IL-1 beta and hemorrhage, and cell groups lining the lamina terminalis in response to salt loading. Challenge-specific induction of NGFI-B expression was detectable in these extrahypothalamic cell groups, though with a lesser sensitivity than that required to reveal NGFI-B induction in the hypothalamus, or c-fos expression in these related afferents. These results establish NGFI-B as a useful adjunct to c-fos, for revealing synaptic and/or transcriptional activation in the magno- and parvocellular neurosecretory systems. Differences in the sensitivity of the two markers in revealing functionally related activation in extrahypothalamic regions speak to general issues concerning the use of immediate-early genes in mapping functional circuitry in the CNS.
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PMID:A comparison of two immediate-early genes, c-fos and NGFI-B, as markers for functional activation in stress-related neuroendocrine circuitry. 825 63

Systemic administration of the cytokine interleukin-1 (IL-1) results in increased secretion of ACTH and corticosterone in rats. The available evidence suggests that the acute effects of IL-1 are exerted ultimately at the level of the hypothalamus to increase corticotropin-releasing factor (CRF) secretion into the hypophyseal portal circulation, and hence the central drive on the pituitary-adrenal system. However, the route(s) and mechanism(s) by which circulating IL-1 gains access to central mechanisms governing pituitary-adrenal output remain poorly understood. In this study, we show that intravenous injection of IL-1 beta provokes time- and dose-dependent increases in the expression of the immediate-early gene c-fos, in identified CRF and oxytocin-producing cells of the paraventricular nucleus of the hypothalamus (PVH). Several cell groups known to be involved in central visceromotor regulation also displayed comparable time- and dose-related activation to systemic IL-1, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala, the lateral parabrachial nucleus, and cell groups of the dorsomedial and ventrolateral medulla. Activation of circumventricular organs, which have been hypothesized to serve as central monitors of circulating IL-1, required doses roughly an order of magnitude above those required to activate CRF neurons in the PVH. Combined immunohistochemical and retrograde tracing experiments revealed many IL-1-responsive cells in the nucleus of the solitary tract and the ventrolateral medulla to be catecholaminergic and to project to the region of the PVH. Discrete and unilateral interruption of ascending catecholaminergic projections from the medulla attenuated IL-1-stimulated increases in Fos immunoreactivity and CRF mRNA in the PVH on the ipsilateral side. Disruption of descending projections from circumventricular structures associated with the lamina terminalis did not affect IL-1-mediated Fos induction in the PVH. We conclude that medullary catecholaminergic projections to the PVH play either a mediating or a permissive role in the IL-1-induced activation of the central limb of the hypothalamo-pituitary-adrenal axis.
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PMID:A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. 830 68

It is well established that corticotropin-releasing hormone (CRH) is a principal neuropeptide which mediates the adrenocorticotropic hormone (ACTH) secretory response to interleukin (IL)-1 in the rat. It has recently been suggested that besides CRH, arginine vasopressin may also play a stimulatory role in IL-1 induced ACTH secretion. However, it remains to be elucidated whether other neuropeptides possessing an ACTH-releasing activity are involved in this neuroendocrine event. Therefore, in this study, we examined possible roles for oxytocin (OT) and cholecystokinin (CCK)-8 in the IL-1-induced ACTH response, utilizing the technique of immunoneutralization of these peptides. For comparison, we examined the effect of CRH immunoneutralization as well. Human recombinant IL-1 beta (50 ng) was given intracerebroventricularly (to the 3rd ventricle) to freely moving male rats 15 min after injecting specific antiserum against CRH, OT, or CCK-8, or normal rabbit serum (control) via the same route. As expected, anti-CRH antibody significantly suppressed the ACTH response to IL-1 beta. Interestingly, anti-OT antibody acted in the same manner, whereas anti-CCK-8 antibody did not. These results suggest that in addition to CRH and arginine vasopressin, OT may also play a significant role in mediating the IL-1 beta-induced ACTH secretion in the rat.
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PMID:Involvement of oxytocin and cholecystokinin-8 in interleukin-1 beta-induced adrenocorticotropin secretion in the rat. 852 Nov 44

Oxytocin (OT) has been shown to be the dominant peptide of the neurohypophysial family expressed by thymic epithelial and nurse cells (TEC/TNC) in various species. Thymic OT is not secreted but, after translocation of a hybrid neurophysin/MHC class I protein, is integrated within the plasma membrane of TEC, thus allowing its presentation to pre-T cells. In order to further demonstrate that thymic OT behaves like a membrane antigen, we assessed the effect of mAbs to OT on cytokine productions by cultures enriched in human TEC. 75-85% pure TEC cultures were prepared from human thymic fragments. Using immunofluorescence and confocal microscopy, ir-OT, ir-interleukin-1 beta (IL-1 beta), ir-interleukin-6 (IL-6) and ir-leukemia inhibitory factor (LIF) could be detected in these TEC cultures. ir-OT was restricted to TEC, while some ir-IL-6 and ir-LIF were also seen in occasional fibroblasts. In basal conditions, ir-IL-6 and ir-LIF (but not ir-OT and ir-IL-1 beta) were detected in the supernatants of human TEC cultures. MAbs to OT induced a marked increase of ir-IL-6 and ir-LIF secretion in TEC cultures. No significant effect was observed using mAbs against vasopressin, mouse immunoglobulins, or control ascitic fluid controls. These data show that OT is fully processed and recognized by specific mAbs at the outer surface of TEC plasma membrane. They further support that thymic OT behaves as the self-antigen of the neurohypophysial family.
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PMID:Cytokine production by human thymic epithelial cells: control by the immune recognition of the neurohypophysial self-antigen. 895 4

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