摘要:

This paper discusses the current evidence supporting the notion that endogenous carbon monoxide (CO) is a modulator of neuroendocrine function. CO is normally formed in the body during the enzymatic catabolism of heme moieties by heme oxygenase (HO). Three HO isoforms have been described to date: HO-1, HO-2 and HO-3. In the brain, CO is principally generated by HO-2 but, in discrete brain areas such as the paraventricular nuclei of the hypothalamus, a role for HO-1 is also possible. Moreover, under pathological conditions, the latter isoform is expressed by activated glial cells. The possible contribution by the recently described HO-3 remains to be established. Once formed, CO exerts its biological effects mainly via the activation of soluble guanylyl cyclase, but alternative signaling mechanisms, such as the activation of cyclo-oxygenase or the inhibition of cytochrome P450, have also been reported. In in vitro studies, the formation of CO within the hypothalamus has been associated with inhibition of the release of hormones such as corticotropin-releasing hormone, arginine vasopressin and oxytocin involved in hypothalamo-pitu-itary-adrenal axis activation and, conversely, with stimulation of luteinising hormone-releasing hormone release, thus suggesting that the gas may have a neuroendocrine role which may be to prevent over-exuberant activation of the hypothalamo-pituitary-adrenal axis and inhibition of reproductive processes within the hypothalamus during stress. At present, however, the possible pathophysiological relevance of the in vitro observations remains to be demonstrated.

ISSN:1021-7401    

DOI:10.1159/000097340

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Lipopolysaccharide (LPS) and homologous cytokines were tested for their effect on core temperature in mice using battery-operated telemetric devices placed in the peritoneal cavity. One microgram LPS injected intraperitoneally (i.p.) induced a biphasic effect on core body temperature (Tc), a rapid decrease in Tc with a peak around 30–45 min followed by a prolonged rise around 150–300 min. When a higher dose of LPS (5 jxg) was used, the hypothermia was increased in magnitude and lasted much longer, and no fever was observed. Both the decrease and the increase in Tc caused by LPS were prevented by pretreating the mice with indomethacin, a cyclooxygenase inhibitor, but not by a nitric oxide synthase inhibitor. Mouse interleukin-1β (mIL-1β, 100 ng, i.p.) induced changes resembling those to LPS, a short-lived decrease in Tc, followed by a small increase. When 1 μg mIL-1β was injected a profound hypothermia lasting more than 3 h was observed. Mouse IL-6 (1 μg) failed to alter core temperature after either intravenous (i.v.) or i.p. administration. Human IL-6 was also ineffective. Recombinant mouse tumor necrosis factor-α (mTNFα) also failed to alter the core temperature of mice when injected at a dose of 1 μg (i.p. or i.v.). However, a higher dose of mTNFα (5 μg i.p.) caused a short-lived decrease in Tc, followed by a small increase. Similar results were obtained with LPS and the cytokines in C57B1/6J mice, except that mIL-1β was ineffective in this strain. These results indicate that the endocrine, neurochemical and behavioral responses to IL-1, IL-6 and TNFα administration cannot be explained by changes in Tc, although they may contribute to them. They also suggest that IL-1β may account for the fever observed following LPS, but that these cytokines are probably not the only factors involved in LPS-induced changes in Tc.

ISSN:1021-7401    

DOI:10.1159/000097341

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Several cytokines produced by immune cells act within the hypothalamus and/ or on the pituitary to produce the pattern of pituitary hormone secretion that characterizes infection. Granulocyte-macrophage colony stimulating factor (GMCSF) was first described as a hematopoietic cytokine; however, its synthesis is also stimulated during infection, and it has been found in glia in the brain. Previous research indicates that interleukin-1 inhibits release of luteinizing hormone-releasing hormone (LHRH) both in vivo and in vitro. In the present study, we determined that GMCSF inhibited the release of LHRH in vitro and evaluated the mechanisms involved. After a 1-hour preincubation in Krebs-Ringer bicarbonate glucose buffer (KRB), medial basal hypothalamic explants were incubated in KRB together with recombinant murine GMCSF for 0.5 h in a Dubnoff metabolic shaker (50 cycles/min) in an atmosphere of 95% O2/5% CO2. LHRH release into the media was determined by radioimmunoassay. At concentrations of 10–12 and 10–11M, GMCSF significantly inhibited LHRH release. There was a U-shaped dose-response curve and LHRH release was not inhibited at lower or higher cytokine concentrations. The inhibition was specific since it was completely blocked by GMCSF antiserum. Since sodium nitroprusside (NP; 300 μM), a releaser of nitric oxide (NO), stimulates LHRH, presumably by acting within the LHRH neurons, we examined the effect of GMCSF (10–11 M) on NP-induced LHRH release. It completely suppressed NP-induced release of LHRH. Bicuculline (10–5M), a γ-aminobutyric acid (GABA) receptor antagonist, partially reversed the inhibitory effects of GMCSF on LHRH release. This dose completely reversed the suppression of LHRH release induced by GABA. The present results indicate that the inhibitory effects of GMCSF on LHRH release are partially caused by blockade of NO-induced LHRH release by its activation of GMCSF receptors on GABAergic neurons. The stimulated release of GABA acts on the GABA-a receptors on the LHRH terminals to inhibit their response to NO. At the end of the experiment, NO synthase (NOS) activity was measured in the tissue homogenate by the citrulline method. NOS activity was highly significantly reduced by GMCSF (10–11M) indicating that part of its suppressive action on LHRH release is mediated by reduction in NOS activity in the medial basal hypothalamus.

ISSN:1021-7401    

DOI:10.1159/000097342

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

We have studied the effect of pancreastatin and its C-terminal fragment (33–49) on mitogen-stimulated T lymphocyte proliferation. In a concentration range from 10–12 to 10–8M they exhibit a dose-dependent stimulatory effect on concanavalin A-induced response with the maximal effect at 10–8M concentration. They were inactive in response to a B-cell mitogen, lipopolysaccha-ride, which points to an involvement of T but not B lymphocytes in their response. Pancreastatin can still produce a stimulatory effect when added 18 h after incubation of cultures with concanavalin A and apparently uses a diacylglycerol independent mechanism. When cells were preincubated for 4, 16 or 24 h with pancreastatin or its fragment and then stimulated with concanavalin A, a ten times lower concentration of peptides was needed (10–9M) to obtain the maximal response. This suggests that resting cells are more sensitive to pancreastatin and its fragment. Both peptides exhibit a very similar pharmacological profile, indicating that the C-terminal part of the molecule is responsible for the effect on T-cell proliferation.

ISSN:1021-7401    

DOI:10.1159/000097343

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Different neuropeptide-containing nerve fibers were investigated to clarify their role in the pathogenesis of Crohn's disease (CD) using immunohisto- and immunocytochemical techniques. Specimens were obtained from patients with CD from grossly affected colonic regions, from biopsies obtained from patients with CD treated with mesalazine and from control individuals. Quantitative analysis was made for the changes of the number of nerve terminals and their vesicle contents. The distribution pattern of all immunoreactive (IR) nerve fibers was similar both in the control and in the surgical specimens as well as in the biopsies obtained. The number of the synapses, the IR nerve fibers and their vesicle content were markedly decreased in the grossly affected colonic regions. Some degenerated axons were found in close proximity to the plasma cells. Immunocytochemistry demonstrated that substance P, vasoactive intestinal polypeptide and somatostatin IR nerve fibers were in direct contact with the plasma cells, lymphocytes and other immunocompetent cells. The gap between the membranes of immunoreactive nerve terminals and immunocompetent cells was 20–200 nm, in a few cases even less. In the mesalazine-treated group the number of the IR nerve terminals as well as their vesicle content was increased. These results suggest that changes in the number of different neuropeptide-containing nerve terminals and their content might alter the neuroimmunological processes, because these peptides are known to be immunoregulators.

ISSN:1021-7401    

DOI:10.1159/000097344

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Administration of intekleukin-1 (IL-1) into the cerebral ventricles produces marked physiological and behavioral effects. However, the precise locations within the central nervous system that mediate these effects have not been determined. Previous studies indicated that IL-1 induces neurophysiological, neurochemical and neuroendocrine changes within the hypothalamic paraventricular nucleus (PVN). These findings suggest that the PVN is also involved in mediating the behavioral effects of IL-1. This hypothesis was tested by examining the effects of administration of IL-1β (10 or 50 ng/rat) or saline, either intracerebroventricularly or into the PVN, on fever and several behavioral parameters. IL-1β, administered into both locations, induced a comparable suppression of motor activity, reduction in food and saccharine consumption, and loss of body weight. The febrile response to IL-1β, assessed by a biotelemetric system, was significantly greater following administration into the PVN than into the lateral ventricle. Additionally, IL-1 administration into adjacent thalamic locations had no febrile or behavioral effects. These findings suggest that the PVN may be one of the brain structures involved in mediating the response to IL-1.

ISSN:1021-7401    

DOI:10.1159/000097345

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Mast cells degranulate when exposed to specific antigens (via surface bound IgE), resulting in the release of numerous pro-inflammatory mediators. Neu-roregulatory substances also activate mast cells, and may effect differential mediator release, without degranulation, suggesting a role for nerves in modulating mast cell activity. We previously investigated the microanatomical relationships of intestinal mucosal mast cells (IMMC with nerves and found extensive associations in the intestinal mucosae of rats and humans. The origins of nerves that contact IMMC have not been determined; however, recent morphological and functional studies suggest the possibility that the vagus nerve might be involved. In the current study we show that vagal afferent fibers (labeled by injecting DiI into the nodose ganglion) penetrate to the tips of jejunal villi; and that some of these nerves make intimate contact with IMMC. These data provide the microanatomical basis for direct neural communication between the central nervous system (CNS) and mast cells in the gastrointestinal mucosa.

ISSN:1021-7401    

DOI:10.1159/000097346

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Since ciliary neurotrophic factor (CNTF) inhibits the production of TNF and activates the hypothalamus-pituitary-adrenal axis (HPAA), we investigated whether CNTF can produce antiinflammatory actions and whether it may act through a central mechanism, using the murine air pouch model of inflammation. In this model, inflammation is evaluated by measuring the induction of TNF and IL-6 as well as cell recruitment in the pouch fluid 24 h after carra-geenan. Intracerebroventricular injection, but not intravenous or local injection of CNTF markedly inhibited inflammation. This was associated with high serum corticosterone levels, and antiinflammatory action was not observed in adrenalectomized mice, indicating that an intact HPAA is required. A CNTF receptor antagonist increased carrageenan inflammation, suggesting that endogenous CNTF might have a centrally mediated antiinflammatory role.

ISSN:1021-7401    

DOI:10.1159/000097347

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Peripheral blood monocytes (PBMCs) obtained from a boy with the neuroim-munodegenerative syndrome of ataxia telangiectasia (AT) failed to aggregate or replicate efficiently when mitogenically activated under serum-depleted conditions. These cells rapidly swelled, then slowly shrank, and flattened as they excreted vesicles containing chromatin. This accelerated cell death with loss of homoadhesiveness could be prevented in vitro in most of the homozygous PBMCs by adding large amounts of autologous serum or by adding mixtures of Th1 cytokines, serum factors, and redox agents. However, even in high-serum media containing added cytokines, 20–30% of the homozygous PBMCs quickly flattened, produced minicells, and died. Since the defective functions of the human ataxia-telangiectasia nuclear kinase gene (ATM) could be bypassed in vitro in these defective AT PMBCs by addition of appropriate cytokines and redox survival factors, it may be possible to slow the progressive losses of ATM-deficient lymphoid cells seen in vivo. Since the neuronal degeneration in AT, as seen in the retrovirus-induced neuroimmu-nodegenerative syndromes, may also be a consequence of impairment of the central and peripheral immune system, it may become possible to prevent the neurodegeneration in AT by using signaling therapies that upregulate the ATM-induced signal deficiencies in the developing immune system.

ISSN:1021-7401    

DOI:10.1159/000097348

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Endogenous opioid peptides and opiates like morphine produce their pharmacological effects through the membrane bound opioid receptors. These receptors belong to a superfamily of G-protein-coupled receptors, all of which possess seven membrane-spanning regions. Structure-activity relationship studies of opioids opened up new avenues for the pharmacological characterization of the opioid receptors. As a further advancement in this direction, molecular cloning has led to the identification of three different types of opioid receptors – OP1 (δ), OP2(Κ) and OP3 (μ) – thereby supporting the results of earlier pharmacological studies which postulated their existence. The three opioid receptors are highly homologous. Consequent to the development of highly specific and selective agonists and antagonists, it was proposed that the three types of opioid receptors could be further categorized into different subtypes. However, the molecular biology data generated so far do not support the presence of the various subtypes of the three well-characterized opioid receptors. Recent strides towards the advancement of our knowledge relating to the molecular biology of these receptors have been reviewed in this article.

ISSN:1021-7401    

DOI:10.1159/000097349

出版商:S. Karger AG    

年代:1997

数据来源: Karger