Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutral endopeptidase (NEP) 24.11 appears to be an important enzyme in both vertebrate and invertebrate autoimmunoregulation. Activation of human or invertebrate immunocytes that express NEP with substrates such as monokines and neuropeptides results in its increased expression, in other words, upregulation. However, since certain neuropeptides are also substrates for NEP, these activated immunocytes will respond to neuropeptides only at higher concentrations, thus downregulating the response. Specifically, in tumor necrosis factor (TNF)-treated immunocytes, we demonstrate the effects of increased NEP expression on altering the stimulatory activities of the neuropeptides met-enkephalin, melanocyte-stimulating hormone and substance P. We demonstrate the significance of NEP in modulating these responses through the use of specific enzyme inhibitors such as phosphoramidon, thiorphan and captopril. Furthermore, we present evidence suggesting that the individual variations seen in immunocytes from both different and the same donors to activating substances may reflect fluctuating levels of NEP expressed in response to endogenous stimuli. These results indicate that NEP is a highly significant factor in controlling the response(s) of certain immunocytes in man and higher invertebrates to the influence of biologically active substances such as monokines and neuropeptides.
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PMID:Autoimmunoregulation: differential modulation of CD10/neutral endopeptidase 24.11 by tumor necrosis factor and neuropeptides. 128 Nov 68

Primary responsibility for the induction of various acute phase reactions has been ascribed to interleukin 1 (IL-1), tumor necrosis factor (TNF), or IL-6, suggesting that these cytokines may have many overlapping activities. Thus, it is difficult to identify the cytokine primarily responsible for a particular biologic effect, since IL-1 and TNF stimulate one another, and both IL-1 and TNF stimulate IL-6. In this work, the contribution of IL-6 in radioprotection, induction of adrenocorticotropic hormone (ACTH), and induction of hypoglycemia was assessed by blocking IL-6 activity. Administration of anti-IL-6 antibody to otherwise untreated mice greatly enhanced the incidence of radiation-induced mortality, indicating that like IL-1 and TNF, IL-6 also contributes to innate resistance to radiation. Anti-IL-6 antibody given to IL-1-treated or TNF-treated mice reduced survival from lethal irradiation, demonstrating that IL-6 is also an important mediator of both IL-1- and TNF-induced hemopoietic recovery. A similar IL-1/IL-6 interaction was observed in the case of ACTH induction. Anti-IL-6 antibody blocked the IL-1-induced increase in plasma ACTH, whereas recombinant IL-6 by itself did not induce such an increase. Anti-IL-6 antibody also mitigated TNF-induced hypoglycemia, but did not reverse IL-1-induced hypoglycemia. It is, therefore, likely that TNF and IL-1 differ in their mode of induction of hypoglycemia. Our results suggest that an interaction of IL-6 with IL-1 and TNF is a prerequisite for protection from radiation lethality, and its interaction with IL-1 for induction of ACTH.
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PMID:Role of interleukin 6 (IL-6) in protection from lethal irradiation and in endocrine responses to IL-1 and tumor necrosis factor. 131 Oct 16

Recent reports show that cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and intravenously administered interleukin-6 (IL-6) stimulate adrenocorticotropic hormone (ACTH) release. Both IL-1 and TNF are known to be potent inducers of IL-6, a monokine produced by activated monocytes and folliculo-stellate cells of the pituitary gland and released from the hypothalamus. To determine the site(s) of action of IL-6 in the control of ACTH release, we injected human recombinant IL-6 into the third brain ventricle (3V) of freely moving, conscious male rats and measured ACTH by RIA. Both 0.05 pmole and 0.25 pmole doses of IL-6 were ineffective to change plasma ACTH in comparison to the values in controls. The maximal IL-6 dose tested of 1.25 pmole increased plasma ACTH within 15 min and the response lasted over 180 min. The effects of IL-6 on plasma ACTH were only partially paralleled by increased rectal temperature which suggests that hypothalamic temperature regulating centers were independent of these actions. To evaluate a possible direct effect on the pituitary, IL-6 was incubated in vitro with hemipituitaries under an atmosphere of 95% O2/5% CO2. After 1 hr of incubation IL-6 failed to cause any change in the secretion of ACTH throughout a concentration range of 10(-15) to 10(-9) M. Increased ACTH secretion into the incubation medium was found only with 10(-13) M IL-6 after a 2-hr incubation. The results support a possible role for IL-6 at both hypothalamic and/or pituitary levels to stimulate ACTH release.
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PMID:Induction of adrenocorticotropic hormone release by interleukin-6 in vivo and in vitro. 131 56

Utilizing push-pull perfusion, we examined the effects of intravenous (iv) administration of human recombinant tumor necrosis factor (TNF)-alpha on the levels of plasma adrenocorticotropin (ACTH) and corticotropin releasing hormone (CRH) in the median eminence (ME) of freely moving male rats. The ME was perfused with artificial cerebrospinal fluid between 11:00 and 14:00 h, and perfusates and blood samples were collected every 20 min. TNF-alpha (1.0 microgram), but not vehicle only, given as an iv bolus at 12:00 h significantly stimulated both plasma ACTH and ME-CRH. The increase in ME-CRH clearly preceded that of plasma ACTH. This is the first to characterize the temporal profile of CRH secretion in the ME after iv administration of TNF-alpha to freely moving rats. These in vivo data strongly suggest that TNF-alpha stimulates ACTH secretion, at least in part, by triggering hypothalamic CRH release. In addition, combined with our previous data obtained by iv administration of human recombinant interleukin-1 under the same experimental condition, the present study also suggests that iv injected TNF-alpha and interleukin-1 may share a common site of action in the brain, such as the ME, to stimulate CRH secretion.
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PMID:Intravenous administration of tumor necrosis factor-alpha stimulates corticotropin releasing hormone secretion in the push-pull cannulated median eminence of freely moving rats. 132 21

The pattern of expression of at least four neuropeptides contained in adrenomedullary chromaffin cells is altered by exposure to the cytokines interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF alpha), alone or in combination with stimulation of other second messenger pathways. Vasoactive intestinal polypeptide (VIP) was elevated 2- to 3-fold by 1 nM IL-1 alpha within 48 h of exposure, while neurotensin and substance P synthesis were unaffected, and met-enkephalin levels were decreased 25-35%. Stimulation of VIP and substance P biosynthesis by forskolin was markedly enhanced by IL-1 alpha, while forskolin stimulation of enkephalin and neurotensin biosynthesis was unaffected. IL-1 alpha amplified the effect of phorbol myristate acetate to increase the VIP content of chromaffin cells, but antagonized phorbol ester-induced elevation of neurotensin levels. TNF alpha also demonstrated a neuropeptide-specific pattern of modulation of second-messenger effects on chromaffin cell neuropeptide levels similar to those seen with IL-1 alpha. The neuroendocrine actions of IL-1 alpha described above, unlike IL-1 action in the immune system, do not appear to be mediated through IL-2 as this cytokine did not affect VIP or enkephalin expression in the presence or absence of protein kinase stimulation. Neither IL-1 alpha nor TNF alpha affected the calcium-coupled stimulation of neuropeptide secretion and biosynthesis that occurs in response to cell depolarization in these and other neuroendocrine cells in vitro and in vivo. These data provide a functional demonstration of IL-1 and TNF receptors in chromaffin cell cultures and suggest a physiological role for cytokine production in the adrenal medulla. Since both the magnitude and direction of neuropeptide synthesis modulation by IL-1 alpha and TNF alpha are highly peptide-specific, it appears that these cytokines do not merely augment second messenger pathways that affect neuropeptide synthesis, but potentially regulate the activity of factors controlling the pattern of neuropeptide gene expression in chromaffin cells.
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PMID:Interleukin-1 alpha and tumor necrosis factor-alpha differentially regulate enkephalin, vasoactive intestinal polypeptide, neurotensin, and substance P biosynthesis in chromaffin cells. 137 39

To examine the response of the hypothalamic-pituitary-adrenal (HPA) axis to severe surgical stress, we measured the immunoreactive plasma levels of corticotropin-releasing hormone (CRH), corticotropin, cortisol, arginine-vasopressin (AVP), atrial natriuretic factor (ANF), neuropeptide Y (NPY), interleukin-1 (IL-1), IL-6, interferon gamma (INF), and tumor necrosis factor-alpha (TNF-alpha) in eight patients with Zollinger-Ellison syndrome (ZES) or mediastinal parathyroid carcinoma, all undergoing major surgery with a standardized anesthetic technique. Blood samples were drawn the morning before surgery, every 10 to 30 minutes throughout surgery (average, 308.7 +/- 15 minutes), and every morning for the next 4 postoperative days (POD). During surgery, plasma CRH concentrations were slightly but not significantly elevated compared with those before surgery and with those of the next 4 POD. However, the values were within the normal range (less than 2.2 pmol/L) and showed 8.9 +/- 0.6 pulses (one pulse every 34.7 +/- 1.6 minutes). Plasma corticotropin, on the other hand, was quite elevated, but was also released in a pulsatile fashion during the surgical procedure (one pulse every 36.7 +/- 1.6 minutes). Most of these secretory episodes of corticotropin were temporally related to those of CRH. Corticotropin returned to basal levels on the first POD and remained so for all 4 POD. Plasma cortisol concentrations increased steadily during surgery and remained elevated the first POD. Cortisol showed 6.2 +/- 1.1 pulses during the operative sampling period (one pulse every 71.8 +/- 13 minutes). Plasma AVP concentrations were also markedly elevated during surgery, but individual secretory pulses were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulsatile activation of the hypothalamic-pituitary-adrenal axis during major surgery. 164 Aug 60

The immune and neuroendocrine systems communicate and maintain homeostasis through various mechanisms, including the use of common signal and recognition molecules and the use of similar processes. This type of integrated network has profound effects on the onset and outcome of certain disease states, including endotoxic shock, in which a cascade of mediators influence the pathophysiologic responses. We have found that some of the common signal molecules shared between the immune and neuroendocrine systems are the peptide hormones adrenocorticotropin (ACTH) and endorphins (END). Our investigations have shown that these molecules are produced in vitro by cells of the immune system treated with various stimuli, including immunological stimuli such as bacterial lipopolysaccharide (LPS; endotoxin), virus infection (Newcastle virus; NDV), and the more classical neuroendocrine stimuli corticotropin-releasing hormone (CRH). We have proposed that the production of END by the peripheral immune system contributes to the pool of opioid peptides associated with the pathophysiology of endotoxic shock. Lymphocytes from LPS-sensitive C3HeB/FeJ mice but not LPS-resistant C3H/HeJ mice produce END and ACTH both in vitro and in vivo after treatment with LPS. Purification of the in vitro produced LPS-induced END from B-lymphocyte spleen cells followed by injections into both LPS-sensitive and -resistant mice elicits changes in body temperature and respiration rate. The spleen cells from the LPS-sensitive mice process ACTH and END differently depending on the stimulus for induction and the cell type in which the processing takes place. CRH or virus induce ACTH 1-39 and beta-END, whereas inductions with LPS yield major products of ACTH 1-22 to 1-26 and gamma-END, products that are for the most part unique to the immune system. We have shown that LPS induces a novel protease that functions optimally at pH 5 to cleave ACTH 1-39 into ACTH 1-22 to 1-26. This enzyme is present in LPS, but not mock or CRH-induced B cells from LPS-sensitive mice. The LPS-resistant mice did not possess this enzyme and therefore produced only the high-molecular-weight pro-opiomelanocortin (POMC)-like molecule. The inability to produce ACTH and END, presumably by their inability to process the precursor, may account, in part, for their lack of response to the LPS. The POMC peptides also may play an indirect role in orchestrating the pathophysiologic response, since both ACTH and END were shown to induce tumor necrosis factor (TNF). Our data strongly suggest that lymphocyte POMC peptides ACTH and END are important mediators in the overall response to endotoxin.
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PMID:Role of leukocyte-derived pro-opiomelanocortin peptides in endotoxic shock. 166 42

We investigated the effects of various hormones and growth factors on aromatase activity in cultured human skin fibroblasts. Several potential trophic factors were tested for their ability to modify basal aromatase activity or the response to dibutyryladenosine 3',5'-cyclic monophosphate and dexamethasone because (i) no endogenous ligand has been identified that is responsible for stimulating aromatase activity in the periphery, and (ii) dexamethasone and cAMP analogs can increase this enzyme's activity in fibroblasts. The effect of insulin and insulin-like growth factors were examined in closer detail because of the clinical association between insulin and hyperandrogenism. Pituitary hormones and hypothalamic releasing factors, such as human ACTH (10 nM), beta-endorphin (10 nM), beta-lipotropin (10 nM), alpha-MSH (10 nM), gamma 3-MSH (10 nM), ovine luteinizing hormone (10 ng/ml), ovine follicle-stimulating hormone (10 ng/ml), ovine thyroid-stimulating hormone (10 ng/ml), rat growth hormone (10 ng/ml), rat prolactin (10 ng/ml), rat corticotropin-releasing factor (10 nM), luteinizing hormone-releasing factor (10 nM), thyrotropin-releasing factor (10 nM), human growth hormone-releasing factor (10 nM), and somatostatin (10 nM), have no significant effects on aromatase activity. Porcine inhibin A (10 ng/ml) and porcine activin AB (10 ng/ml), two ovarian hormones with structural transforming homology to transforming growth factor-beta, also have no effect on aromatase activity. Although basic fibroblast growth factor (1-100 ng/ml), acidic fibroblast growth factor (1 ng/ml), epidermal growth factor (1 ng/ml), platelet-derived growth factor (1 ng/ml), tumor necrosis factor (1 ng/ml), and transforming growth factor-beta 1 (1 ng/ml) have no effect on basal aromatase activity in human skin fibroblasts, all of these growth factors inhibited the ability of dibutyryladenosine 3',5'-cyclic monophosphate to stimulate aromatase activity. In contrast, both insulin (100 pg/ml-10 ng/ml) and insulin-like growth factor-1 (1-100 ng/ml) had no effect on cAMP-stimulated aromatase but potentiated the action of dexamethasone (100 nM). Thus, there is a clear distinction between the effects of dexamethasone and cAMP on peripheral aromatase. On the basis of the results presented here, it is interesting to speculate that the hyperandrogenism that is often associated with insulin resistance may be due to a combination of growth factor-mediated inhibition of aromatase activity and the failure of peripheral tissues to respond to insulin and metabolize androgens to estrogens.
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PMID:Growth factor-mediated regulation of aromatase activity in human skin fibroblasts. 167 98

The list of shock mediators currently comprises more than 150 candidates. A careful analysis using the criteria of Koch-Dale together with decision trees for exclusion of bias revealed that only histamine, C5a, beta-endorphin, tumor necrosis factor (TNF) thromboxane B2, platelet-activating factor (PAF), and oxygen free radicals are shown to be causally associated with shock symptoms. Although experimental studies with inhibitors of these mediators were convincing, there is still a lack of evidence under clinical conditions (exception histamine: anaphylactic shock). Combinations of antagonists against different causal mediators are the most promising future approaches.
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PMID:[Mediators and their antagonists in shock therapy]. 172 95

Cytokines (CKs) are involved in the mechanisms of sleep induction, and, in particular, interleukin-1 (IL-1) and tumor necrosis factor-alpha seem to play an important role in the slow-wave sleep. Here are reported two cases of normal sleep and altered sleep in which plasma levels of IL-1 beta have been determined. In the subject with a normal sleep a dramatic increase of this CK has been observed, while beta-endorphin levels were reduced. In the light of these findings, the role of sleep in the host protection is discussed.
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PMID:Somnogenic cytokines with special reference to interleukin-1. 180 52


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