Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immediate responses to aerosolized staphylococcal enterotoxin B (SEB) in respiratory toxic shock were studied in the circulation of rhesus monkeys with low antibody levels following immunization with SEB toxoid-containing microspheres. Both the surviving and dying monkeys had toxic shock syndrome 4-48 h after SEB challenge and all showed three distinctive patterns of immediate responses. The first pattern, characterized by the responses of all T cells, HLA-DRlo cells, monocytes, IL-2R+ cells, IFN-gamma, and augmented lymphocyte mitotic responses to lipopolysaccharide (LPS) and SEB in culture, was a rapid increase at 20 min followed by a quick decrease at 90 min to approximately the original levels. The second pattern, which included responses of HLA-DRhi cells, NK cells, adrenocorticotropic hormone (ACTH) and cortisol, was characterized by a moderate decrease at 20 min and a further decrease at 90 min. The third pattern, the inverse of the second pattern, including responses of polymorphonuclear leukocytes (PMN), concanavalin A (Con A) mitogenesis, IL-6 and IL-2, was a moderate increase at 20 min and a further increase at 90 min. Between the surviving and dying monkeys, the responses of T cells, HLA-DRhi cells, PMN and cortisol did not differ significantly, suggesting that they are the basic causes that initiated toxic shock. However, significant differences were seen in the responses of HLA-DRlo cells, monocytes, IL-2R+ cells and lymphocyte mitogenesis in culture at 20 min, and of Con A mitogenesis, NK cells, IL-2, IL-6 and ACTH at 90 min. These different responses are apparently the exacerbating causes of death of the monkeys. All together, the immediate responses seem to be caused by the combined effects of SEB superantigenicity, activation of NK cells and non-lymphoid cells, and depression of the neuroimmune defense system.
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PMID:Immediate responses of leukocytes, cytokines and glucocorticoid hormones in the blood circulation of monkeys following challenge with aerosolized staphylococcal enterotoxin B. 946 10

During infection, bacterial products, such as lipopolysaccharide (LPS), and viral products release cytokines from immune cells. These cytokines reach the brain by several routes. Furthermore, cytokines such as interleukin-1 (IL-1) are induced in central nervous system neurons by systemic injection of LPS. These cytokines determine the pattern of hypothalamic-pituitary secretion which occurs in infection. IL-2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (NOS). The nitric oxide (NO) released diffuses into corticotropin-releasing hormone (CRH)-secreting neurons and releases CRH. IL-2 also acts in the pituitary to stimulate adrenocorticotropic hormone secretion. On the other hand, IL-1 alpha blocks the NO-induced release of luteinizing-hormone-releasing hormone (LHRH) from neurons, thereby blocking pulsatile luteinizing hormone (LH), but not follicle-stimulating hormone release, and also inhibiting sexual behavior which is induced by LHRH. IL-1 alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) block the response of the LHRH terminals to NO. GM-CSF inhibits LHRH release by acting on its receptors on gamma-aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABA-A receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. This concept is supported by a blockade of GM-CSF-induced suppression of LHRH release from medial basal hypothalamic explants by the GABA-A receptor blocker, bicuculline. IL-1 alpha inhibits growth hormone (GH) release by inhibiting GH-releasing hormone release mediated by NO and stimulating somatostatin release, also mediated by NO. IL-1 alpha-induced stimulation of prolactin release is also mediated by intrahypothalamic action of NO which inhibits release of the prolactin-inhibiting hormone, dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase liberating cyclic guanosine monophosphate and activation of cyclooxygenase and lipoxygenase, with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in the release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL-1 beta, also act in the anterior pituitary gland, at least in part, via induction of inducible NOS. The NO produced alters the release of anterior pituitary hormones.
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PMID:Nitric oxide controls the hypothalamic-pituitary response to cytokines. 948 1

Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of alpha-MSH (1-13), alpha-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon gamma (IFN-gamma). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-gamma, microglia increased release of alpha-MSH. Production of TNF-alpha, IL-6, and NO was greater in activated microglia after innmunoneutralization of endogenous alpha-MSH. The results suggest that alpha-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of pro-inflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.
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PMID:Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia. 962 Jun 67

Prenatal alcohol exposure has been shown to produce hyperresponsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to immune challenges. Because cytokines, which are released in response to immune challenges, are known to activate the HPA axis, this study determined whether altered release of cytokines contribute to the HPA hyperresponsiveness to immune challenges observed after prenatal alcohol exposure. Pregnant dams were exposed to alcohol vapors (6-7 hr daily) between days 7 and 18 of gestation. At postnatal days 45 and 60, control (C) and prenatal alcohol-exposed (E) offspring were subjected to three different types of immune challenges: injections of interleukin-1beta or endotoxin (lipopolysaccharide), or turpentine-induced tissue injury. We observed the expected higher plasma adrenocorticotropic hormone and corticosterone levels in E compared with C rats, and this HPA hyperresponsiveness was greater in E females compared with E males. Plasma tumor necrosis factor-alpha or interleukin-6 responses were comparable in the C and E groups. Females exhibited significantly higher corticosterone, tumor necrosis factor-alpha, and interleukin-6 responses than males. These results indicate that (1) prenatal alcohol exposure produces HPA hyperresponsiveness to immune challenges; (2) prenatal alcohol treatment does not influence the release of cytokines to immune challenges; and (3) there are gender differences in the secretory pattern of corticosterone and cytokines to immune challenges. Therefore, these data do not support the hypothesis that cytokines play a role in the hyperresponsiveness of the HPA axis to immune challenges observed after prenatal alcohol exposure.
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PMID:Effects of prenatal exposure to alcohol on the release of adenocorticotropic hormone, corticosterone, and proinflammatory cytokines. 1002 3

We have previously described the regulation of interleukin-1 receptor antagonist (IL-1ra) protein secretion and expression by IL-1, glucocorticoids and corticotropin-releasing hormone in monocytes in culture. In the present work, we analyze the direct effect of adrenocorticotropic hormone (ACTH) and beta-endorphin on the expression and secretion of IL-1ra by human monocytes in culture. ACTH exerted a dose-dependent inhibitory effect on lipopolysaccharide (LPS)-induced IL-1ra production and mRNA expression. Basal IL-1ra levels were not affected by treatment with any ACTH dose. In contrast, on human monocytes, beta-endorphin at concentrations as low as 10 pg/ml produced an increase of basal IL-1ra protein secretion and mRNA expression, this effect being reverted by pretreatment with naloxone. No effect of beta-endorphin was observed either in IL-1ra mRNA expression or protein secretion when cells were treated with LPS. The different effects of ACTH and beta-endorphin could account for their differential contribution to the inflammatory response: while ACTH contributes to the glucocorticoid overall control of the inflammatory response, beta-endorphin exerts an inhibitory tone on the resting IL-1 system. Because IL-1ra is essential in setting the level of monocyte and inflammatory response its differential regulation by the HPA axis hormones contributes to regulating the IL-1/inflammatory temporal response.
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PMID:Differential regulation of interleukin-1 receptor antagonist by proopiomelanocortin peptides adrenocorticotropic hormone and beta-endorphin. 1047 56

Pregnancy and lactation are times of prolonged physiological changes affecting the neuroendocrine and immunological systems. One well-characterized change is the neuroendocrine hyporesponsiveness to acute stressful stimuli. We have now designed studies to see whether there is an alteration in the response of the hypothalamic-pituitary-adrenal (HPA) axis to an immunological inflammatory challenge and to ascertain whether lactating animals show altered neural and endocrine responses to inflammatory stimuli. Lactating (day 9-12 postpartum) or virgin control Sprague-Dawley female rats were injected with either 200 microg of endotoxin (lipopolysaccharide, LPS ) or sterile saline given i.p. Trunk blood or jugular blood was collected from the animals at 2 h or hourly over 6 h after injection. Both plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations were significantly higher in saline treated lactating animals compared with the virgin group. LPS significantly elevated circulating levels of plasma ACTH and corticosterone in both virgin and lactating animals compared with saline controls, however, hormone responses to LPS were significantly reduced in lactating animals relative to virgin controls. Corticosterone-binding globulin concentrations were lower in lactating animals compared to virgin animals and LPS decreased concentrations in virgin, but not lactating rats. Analysis of cfos mRNA in the paraventricular nucleus (PVN) of the hypothalamus revealed that 2 h following injection there was a increase in cfos expression only in the virgin animals treated with LPS, compared to all other treatment conditions. Corticotropin-releasing hormone (CRH) mRNA expression was overall greater in virgin animals, but was increased to similar extent in both virgin and lactating animals treated with LPS. Primary arginine vasopressin (AVP) mRNA transcripts were increased 2 h following LPS injection, but a greater increase in expression was seen in virgin animals. These data demonstrate that there is a lower level of free circulating glucocorticoid in response to inflammatory stimuli and suggests that communication between the immune and endocrine systems may be altered during lactation.
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PMID:The hypothalamic-pituitary-adrenal axis response to endotoxin is attenuated during lactation. 1052 Jan 36

Interleukin-1beta (IL-1beta) plays a key role in immune, behavioral and neuroendocrine responses to inflammation or infection. IL-1beta could also be involved in the response of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Mature IL-1beta derives from a 31-kD precursor (pro-IL-1beta) that is processed by IL-1beta-converting enzyme (ICE). Mice in which the ICE gene has been nullated by homologous recombination were used to investigate the role of IL-1beta in the HPA axis response. Plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) in response to an intraperitoneal injection of 5 microg lipopolysaccharide (LPS) were similar in ICE-deficient mice and wild-type (WT) controls. In contrast, plasma ACTH response to restraint or to 200 ng of rat recombinant IL-1beta (rrIL-1beta) was higher in ICE-deficient mice as compared to WT animals. This hyperreactivity of the HPA axis in ICE knockout mice appears not to be related to the production of plasma IL-1beta or IL-6, which was similar to that of WT mice after rrIL-1beta injection. After lipopolysaccharide, ICE-deficient mice exhibited a smaller increase in plasma-immunoreactive IL-1beta and IL-6 as compared to WT controls. After restraint stress neither increase in plasma IL-1beta nor IL-6 was observed. The mechanisms responsible for the increased reactivity of the HPA axis in ICE-deficient mice may result from a higher sensitivity of the HPA axis to inflammatory cytokines or to cleavage products of pro-IL-1beta processed by non-ICE proteases.
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PMID:Activation of the hypothalamic-pituitary-adrenal axis in IL-1 beta-converting enzyme-deficient mice. 1081 Feb 51

It is well recognized that the reciprocal interaction established between the immune and neuroendocrine systems is crucial for the homeostatic adaptation of individuals during septicemia. In the present study, using an in vivo rat model, we investigated the degree of participation of central and peripheral epinergic systems in the modulation of the hypothalamic-pituitary-adrenal and immune axes' functions during endotoxemia. For this purpose, acute endotoxemia was induced in adult male rats pretreated intraperitoneally with either different inhibitors of phenylethanolamine-N-methyltransferase (PNMT) [which are active either peripherally (SKF 29661) or both peripherally and centrally (SKF 64139), thus lowering epinephrine (EPI) synthesis] or vehicle only (CTRL). Twelve hours after pretreatment, animals were intraperitoneally injected with vehicle alone (basal) or vehicle containing bacterial lipopolysaccharide (LPS) and sacrificed 2 h later. A significant (p < 0.05 vs. the respective basal value) hypoglycemia was found in all groups studied. No pretreatment modified basal plasma adrenocorticotropic hormone (ACTH), glucocorticoid and cytokine concentrations. Endotoxin-stimulated ACTH secretion was severalfold (p < 0.05) higher than the respective basal value in CTRL and in SKFs-pretreated rats; however, the plasma ACTH levels after LPS were significantly (p < 0.05 vs. CTRL and SKF-29661 values) reduced in SKF-64139-pretreated rats. All groups studied showed an appropriate adrenal response to endotoxin challenge. Although no differences were found in basal anterior pituitary (AP) ACTH content among groups, LPS treatment significantly (p < 0.05 versus the respective basal value) decreased AP ACTH in CTRL and SKF 29661 groups. No pretreatment modified the basal medial basal hypothalamus (MBH) corticotropin-releasing hormone (CRH) content. Conversely, SKF 64139 pretreatment significantly (p < 0.05 vs. CTRL and SKF 29661 values) reduced basal median eminence (ME) CRH content, and LPS administration significantly (p < 0.05) decreased ME CRH in CTRL and SKF-29661-pretreated rats. SKF 64139 pretreatment significantly (p < 0.05) enhanced basal MBH and ME arginine vasopressin (AVP) contents. LPS administration significantly (p < 0.05) decreased MBH AVP in CTRL and SKF-29661-pretreated rats and diminished (p < 0.05 vs. basal values) ME AVP in all groups. The plasma tumor necrosis factor alpha (TNFalpha) concentrations were enhanced severalfold (p < 0.05 vs. basal values) after LPS treatment in CTRL rats, but not in SKFs-treated animals. In order to explore the reduced cytokine release after LPS in PNMT-inhibited rats, additional ex vivo experiments were performed by using peripheral mononuclear cells (PMNC) from both CTRL and SKF-29661-pretreated rats. The results of these experiments confirmed an immune dysfunction after inhibition of peripheral EPI synthesis; in fact, basal and concanavalin-A-stimulated TNFalpha secretions were significantly (p < 0.05) lower in SKF-29661-treated than in CTRL PMNC, while, interestingly, addition of EPI (10(-7) M) to the medium fully restored these effects. These data demonstrate that: (1) the mechanism whereby LPS-induced hypoglycemia was independent of epinergic activity; (2) selective central inhibition of epinergic function reduced endotoxin-stimulated ACTH secretion, an effect that could mainly be due to a decrease in CRH-ergic activity; (3) the central epinergic system positively and negatively modulates CRH- and AVPergic functions, respectively, and (4) inhibition of peripheral PNMT activity reduced immune system function in vivo and ex vivo. It is further suggested that low peripheral levels of EPI could be beneficial for the body's defense mechanisms during endotoxic shock.
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PMID:Modulatory role of the epinergic system in the neuroendocrine-immune system function. 1096 35

During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin-1 (IL-1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic-pituitary secretion that characterizes infection. IL-2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin-releasing hormone (CRH)-secreting neurons and releases CRH. IL-2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL-1 alpha blocks the NO-induced release of luteinizing hormone-releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle-stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL-1 alpha and granulocyte macrophage colony-stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on gamma-aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. IL-1 alpha inhibits growth hormone (GH) release by inhibiting GH-releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL-1 alpha-induced stimulation of PRL release is also mediated by intrahypothlamic action of NO, which inhibits release of the PRL-inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase-liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase (COX) and lipoxygenase (LOX) with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL-1 beta, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of ACTH. The adipocyte hormone leptin, a member of the cytokine family, has largely opposite actions to those of the proinflammatory cytokines, stimulating the release of FSHRF and LHRH from the hypothalamus and FSH and LH from the pituitary directly by NO.
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PMID:The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. 1126 67

The influence of social disruption stress (SDR) on the susceptibility to endotoxic shock was investigated. SDR was found to increase the mortality of mice when they were challenged with the bacterial endotoxin lipopolysaccharide (LPS). Histological examination of SDR animals after LPS injection revealed widespread disseminated intravascular coagulation in the brain and lung, extensive meningitis in the brain, severe hemorrhage in the lung, necrosis in the liver, and lymphoid hyperplasia in the spleen, indicating inflammatory organ damage. In situ hybridization histochemical analysis showed that the expression of the glucocorticoid receptor mRNA was down-regulated in the brain and spleen of SDR animals while the ratio of expression of AVP/CRH-the two adrenocorticotropic hormone secretagogue, increased. After LPS injection, the expression of pro-inflammatory cytokines, IL-1beta and TNF-alpha, was found significantly higher in the lung, liver, spleen, and brain of the SDR mice as compared with the LPS-injected home cage control animals. Taken together, these results show that SDR stress increases the susceptibility to endotoxic shock and suggest that the development of glucocorticoid resistance and increased production of pro-inflammatory cytokines are the mechanisms for this behavior-induced susceptibility to endotoxic shock.
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PMID:Social stress increases the susceptibility to endotoxic shock. 1128 52


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