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)

Bacterial lipopolysaccharide (LPS) and corticotropin releasing hormone (CRH) plus arginine vasopressin (AVP) induce immunoassayable (1-13)ACTH (alpha MSH) from mononuclear leukocytes. We studied the ability of LPS and CRH + AVP to in vitro stimulate native ACTH (not alpha MSH) and substance P (SP) production and thymidine incorporation in human mononuclear leukocytes. Neither CRH + AVP nor LPS stimulated detectable amounts of intracellular or extracellular ACTH (less than 15 pg/8 x 10(6) cells or total medium) or SP (less than 50 pg/8 x 10(6) cells or total medium) at 1, 2, 3 or 4 days of incubation. LPS, but not CRF + AVP, increased the amount of 3H-thymidine incorporation over controls. This data questions the importance of an immunoadrenal axis and the synthesis of SP by mononuclear leukocytes.
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PMID:Corticotropin releasing hormone and arginine vasopressin stimulation of ACTH and substance P in human mononuclear leukocytes. 169 18

The mechanisms through which endotoxin stimulates the hypothalamic-pituitary-adrenal axis are not well understood. In the studies reported here we tested the hypothesis that endotoxin increases plasma ACTH levels by releasing interleukin-1 (Il-1). Two experimental tools reported to interfere with the biological activity of IL-1 were used: antibodies directed against IL-1 receptors and alpha MSH. In a first series of experiments, adult male mice were injected with a lipopolysaccharide (LPS; 25 micrograms), antibodies against IL-1 receptor, alpha MSH (1-30 micrograms), or LPS and either IL-1 antibodies or alpha MSH. All treatments were administered ip. The endotoxin LPS caused a marked increase in plasma ACTH levels, measured 6 h later. Both alpha MSH and the Il-1 receptor antibodies, while having no effect by themselves, significantly (P less than or equal to 0.01) blocked LPS-induced ACTH release. In a second series of experiments, mice were injected ip with 500 ng recombinant human (rh) Il-1 alpha or 100 ng rhIl-1 beta in the presence or absence of alpha MSH (1-30 micrograms, ip). While not altering ACTH secretion induced by rhIl-1 alpha, 10-30 micrograms alpha MSH significantly (P less than or equal to 0.01) interfered with the effect of rhIl-1 beta. These results suggest 1) that endotoxin activates the hypothalamic-pituitary-adrenal axis through a mechanism involving the activation of interleukin-1 receptors; and 2) that the effect of rhIl-1 beta, but not -alpha, on ACTH secretion by the mouse can be partially blocked by alpha MSH.
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PMID:In the mouse, the activation of the hypothalamic-pituitary-adrenal axis by a lipopolysaccharide (endotoxin) is mediated through interleukin-1. 255 27

Antipyretic properties have been ascribed to arginine vasopressin (AVP), and the site where its antipyretic effects are mediated in the brain was identified as the ventrolateral septum of the limbic system. In guinea pigs, the majority of AVP projections to the septum originate from parvocellular neurons of the hypothalamic paraventricular nucleus (PVN). Electrical stimulation of the PVN with 10-s trains of current pulses (duration 1 ms, frequency 20 Hz, amplitude 8 V, current 0.205 +/- 0.017 mA) reduced the febrile response to an intramuscular injection of 20 micrograms/kg lipopolysaccharide (LPS from Escherichia coli, 0111: B4) by 54% compared with unstimulated animals. This reduction in fever by electrical PVN stimulation was partly reversed by a simultaneous intraseptal microinfusion of the vasopressinergic V1-receptor antagonist d(CH2)5[Tyr(Met)2]AVP at a concentration of 10(-5) mol for 6 h with an infusion speed of 0.1 microliter/min. We further investigated the effects of intraseptal microinfusions or systemic infusions of the gamma-melanocyte-stimulating hormone (gamma-MSH), a derivative of the proopiomelanocortin, on LPS-induced fever. Intraseptal microinfusions of gamma-MSH at a concentration of 10(-5) mol/l for 6 h with an infusion speed of 0.1 microliter/min caused a 38% reduction in fever. A significantly greater 57% reduction in fever was observed when the intraseptal microinfusion of gamma-MSH was combined with electrical stimulation of the PVN (for parameters see above). A systemic infusion of 0.261 mumol gamma-MSH for 6 h reduced LPS fever to approximately 50% compared with animals infused with vehicle (0.9% saline).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antipyresis caused by stimulation of vasopressinergic neurons and intraseptal or systemic infusions of gamma-MSH. 814 22

alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from pro-opiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by murine macrophages, an influence believed to reflect activation of an autocrine circuit in these cells, one that is based on production and release of alpha-MSH and subsequent stimulation of melanocortin receptors. We found that THP-1 cells, human monocytic cells, produced alpha-MSH; this production was increased by interleukin-6, tumor necrosis factor a, or concanavalin A. These cells also expressed the gene for the human alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells produced little nitrite in response to interferon-gamma (IFN-gamma) and lipopolysaccharide, and a-MSH inhibited this production only slightly. However, production of neopterin, a presumed primate homologue of nitric oxide in lower animals, was increased in THP-1 cells stimulated with INF-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circuit based on alpha-MSH occurs in human monocyte/macrophages much as in murine macrophages. alpha-MSH-induced modulation of specific inflammatory mediators/cytotoxic agents appears to differ depending on the importance of the mediators in the myelomonocytic cells of different species.
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PMID:alpha-MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line. 860 97

The importance of melanocortin peptides to host responses was recognized with the observation of the antipyretic effect of centrally administered alpha-melanocyte stimulating hormone (alpha-MSH). It is now clear that this neuropeptide also exerts remarkable antiinflammatory activity via direct actions on peripheral host cells, descending neurogenic antiinflammatory pathways stemming from CNS melanocortin receptors, and local actions on receptors that control inflammation within the brain. Recent studies of the latter influence indicate that alpha-MSH inhibits brain tumor necrosis factor-alpha (TNF-alpha), previously linked to human neurodegenerative diseases, induced by local injection of lipopolysaccharide. Ischemia/reperfusion of the brain, a model of stroke, induces inflammation marked by disturbance of CNS function. alpha-MSH given systemically modulates disturbances of auditory evoked potentials induced by ischemia/reperfusion in the posterior circulation. Such influences of the peptide may occur through inhibition of inflammatory agents produced by glia: alpha-MSH 1-13 and 11-13 modulate TNF-alpha and nitric oxide produced by activated murine microglia, and TNF-alpha produced by human astrocytes. Because glia can secrete alpha-MSH and express melanocortin receptors, they may, like peripheral macrophages, contain autocrine regulatory circuits based on the peptide. alpha-MSH thus modulates both fever and inflammation in the brain by acting on local melanocortin receptors.
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PMID:Peptide modulation of fever and inflammation within the brain. 991 65

Inflammation and microbial infection produce symptoms, including fever, anorexia, and hypoactivity, that are thought to be mediated by endogenous proinflammatory cytokines. Melanocortins are known to act centrally to suppress effects on fever and other sequelae of proinflammatory cytokine actions in the central nervous system, but the roles of melanocortins in anorexia and hypoactivity occurring during the acute phase response are unknown. The present study was designed to determine the effects of exogenous and endogenous alpha-melanocyte stimulating hormone (alpha-MSH) on lipopolysaccharide (LPS)-induced anorexia in relation to their effects on fever. Rats were fasted overnight to promote feeding behavior, then injected intraperitoneally with LPS (100 micrograms/kg ip), followed 30 min later by intracerebroventricular injection of either alpha-MSH or the melanocortin receptor subtype 3/subtype 4 (MC3-R/MC4-R) antagonist SHU-9119. Food intake, locomotor activity, and body temperature (Tb) were monitored during the ensuing 24-h period. Each of two intracerebroventricular doses of alpha-MSH (30 and 300 ng) potentiated the suppressive effects of LPS on food intake and locomotion, despite the fact that the higher dose alleviated LPS-induced fever. In control rats that were not treated with LPS, only the higher dose of alpha-MSH significantly inhibited food intake, and Tb and locomotor activity were unaffected. To assess the roles of endogenous central melanocortins, LPS-treated rats received intracerebroventricular SHU-9119 (200 ng). Central MC3-R/MC4-R blockade did not affect Tb or food intake in the absence of LPS treatment, but it reversed the LPS-induced reduction in 24-h food intake and increased LPS-induced fever without altering the LPS-induced suppression of locomotion. Taken together, the results suggest that exogenous and endogenous melanocortins acting centrally exert divergent influences on different aspects of the acute phase response, suppressing LPS-induced fever but contributing to LPS-induced anorexia and hypoactivity.
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PMID:Role of central melanocortins in endotoxin-induced anorexia. 1007 Jan 49

The pro-opiomelanocortin-derived peptide alpha-melanocyte-stimulating hormone (alpha-MSH) mediates broad anti-inflammatory and immunomodulatory effects, which include inhibition of the production and release of proinflammatory cytokines and nitric oxide (NO) from macrophages. We investigated the effects of alpha-MSH, alpha-MSH(1-10), and alpha-MSH(11-13) on NO production and nuclear factor-kappaB (NF-kappaB) translocation in RAW 264.7 macrophages. After stimulation of the cells with bacterial lipopolysaccharide/interferon-gamma (LPS/IFN-gamma), all three peptides inhibited NO production with an order of potency alpha-MSH > or = alpha-MSH(11-13) > alpha-MSH(1-10). All three MSH peptides inhibited NF-kappaB nuclear translocation with the maximal effect of alpha-MSH and alpha-MSH(11-13) being seen in the range 1 nM-1 microM, and that of alpha-MSH(1-10) at 1 microM. By use of (125)I-(Nle(4),D-Phe(7))alpha-MSH(NDP-MSH) radioligand binding, MC(1) receptor-binding sites were demonstrated on RAW 264.7 cells. alpha-MSH and alpha-MSH(1-10) competed with the (125)I-NDP-MSH binding at these MC(1) receptor-binding sites, but alpha-MSH(11-13) even in concentrations up to 1 mM did not. Moreover, alpha-MSH and alpha-MSH(1-10) caused powerful stimulation of cyclic 3',5'-adenosine monophosphate (cAMP) in the RAW 264.7 cell, whereas alpha-MSH(11-13) was ineffective. Forskolin stimulated cAMP and inhibited NO production to the same extent as alpha-MSH and alpha-MSH(1-10), but did not modify the translocation of NF-kappaB. Whereas the protein kinase A inhibitor H89 did not modify the effect of alpha-MSH on NF-kappaB translocation, H89 caused a partial inhibition of the inhibitory effect of alpha-MSH, alpha-MSH(1-10), alpha-MSH(11-13), and forskolin on NO production. In addition alpha-MSH, alpha-MSH(1-10), alpha-MSH(11-13), and forskolin also inhibited the activity of an NF-kappaB-dependent luciferase reporter and these effects were partially counteracted by H89. We suggest that melanocortin peptides act via dual mechanisms of action: one cAMP-independent and causing inhibition of NF-kappaB translocation and the other dependent on MC(1) receptor/cAMP activation.
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PMID:Effects of melanocortin peptides on lipopolysaccharide/interferon-gamma-induced NF-kappaB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. 1123 5

Alpha-melanocyte-stimulating hormone (alpha-MSH), a neuroimmunomodulatory peptide of ancient origin, is known to be involved in the control of host responses. In inflammatory cells, in the periphery and within the central nervous system, alpha-MSH modulates the production and action of proinflammatory cytokines. This broad influence occurs via endogenous alpha-MSH (melanocortin) receptors. The key to this anti-inflammatory influence is inhibition of NF-kappa B. Indeed alpha-MSH inhibits activation of this nuclear factor through preservation of I kappa B alpha, which binds to NF-kappa B and prevents its migration to the nucleus. Cells transfected with alpha-MSH plasmid vector are resistant to challenge with bacterial lipopolysaccharide. The peptide also act on central melanocortin receptors to modulate inflammation in the periphery. In brief, alpha-MSH and certain of its fragments such as alpha-MSH [11-13] KPV modulate inflammation via three general actions: direct actions on peripheral host cells; actions on inflammatory cells within the brain to modulate local reactions; and descending neural anti-inflammatory pathways that control inflammation in peripheral tissues.
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PMID:The neuroimmunomodulatory peptide alpha-MSH. 1126 47

Central autonomic and neuroendocrine activities are important components of the host response to bacterial inflammation. We demonstrate that intravenous infusion of gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH), a potent autonomic regulating peptide, prevents lipopolysaccharide (LPS)-induced hypotension and tachycardia, and modulates the ACTH response to endotoxin. In the hypothalamic paraventricular nucleus, a major neuroendocrine and autonomic center, gamma(2)-MSH inhibits LPS-induced increases in CRF mRNA levels, but does not suppress LPS-augmented arginine vasopressin heteronuclear RNA expression. In the locus coeruleus, a brainstem noradrenergic center, gamma(2)-MSH inhibits LPS-induced increases in tyrosine hydroxylase mRNA levels. Gamma(2)-MSH inhibits LPS-induced IL-1beta gene expression in the brain, pituitary and thymus, and prevents increases in plasma NO levels. These findings reveal that gamma(2)-MSH attenuates systemic inflammatory responses to endotoxin and suggest that modulation of central autonomic and neuroendocrine activities by gamma(2)-MSH contributes to its anti-inflammatory effects.
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PMID:Gamma(2)-melanocyte-stimulating hormone suppression of systemic inflammatory responses to endotoxin is associated with modulation of central autonomic and neuroendocrine activities. 1169 21

The pro-opiomelanocortin-derived peptide alpha-melanocyte stimulating hormone (alpha-MSH) mediates many diverse physiological actions, including anti-inflammatory and immunomodulatory effects. However, little is known about the physiological roles of the other melanocortins, beta- and gamma-MSH. Here, we investigated the effects of melanocortin peptides in an in vivo neuroinflammation model. Six hours following intracisternal (i.c.) administration of 10 microg lipopolysaccharide (LPS) to mice a five-fold increase in the nitric oxide (NO) level was seen in the animals' brains, when detected by electron paramagnetic resonance (EPR). All tested melanocortins, alpha-, beta-, gamma1- and gamma2-MSH (0.001-10 nmol/mouse i.c.), dose dependently reduced the LPS induced increases in brain NO, with an order of effectiveness: beta-MSH > or = gamma1-MSH=gamma2-MSH>alpha-MSH. Our results suggest specialized functions of beta- and gamma-MSH melanocortins in inflammatory signal modulation in the brain.
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PMID:Beta- and gamma-melanocortins inhibit lipopolysaccharide induced nitric oxide production in mice brain. 1464 65


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