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)

The neuropeptide alpha-melanocyte stimulating hormone [alpha-MSH(1-13)] occurs in the pituitary, brain, skin and other tissues and receptors for this molecule are likewise widespread. In previous research, this tridecapeptide, which shares its amino acid sequence with ACTH(1-13), was shown to have both potent antipyretic activity and a role in the endogenous control of the febrile response. alpha-MSH(1-13) and its COOH-terminal tripeptide were subsequently found to inhibit inflammation induced by general stimuli such as topical application of an irritant. The aim in the present experiments was to determine if these peptides can inhibit acute inflammatory responses induced in mice by injection of individual cytokines, endogenous pyrogen (EP), a natural cytokine mixture, and other mediators of inflammation. Inflammation induced in the mouse ear by rIL-1 beta, rIL-6 or rTNF-alpha was inhibited by alpha-MSH and a D-valine-substituted analog of alpha-MSH(11-13) whereas substantial doses of alpha-MSH(1-13) did not alter inflammation induced by LTB4, PAF and IL-8. Both peptides inhibited edema caused in the mouse paw by local injection of EP. The results indicate that alpha-MSH molecules antagonize the actions of certain cytokine mediators of inflammation, consistent with previous observations of anti-cytokine activity of these peptides. Failure to inhibit edema caused by LTB4, PAF and IL-8 suggests that, in inflammation induced by general stimuli, such as EP, the peptides act prior to the release of these mediators of the inflammatory response. Because of the anticytokine/anti-inflammatory actions of the alpha-MSH molecules they may be useful in understanding the cytokine network and for treatment of inflammatory diseases.
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PMID:Alpha-MSH peptides inhibit acute inflammation induced in mice by rIL-1 beta, rIL-6, rTNF-alpha and endogenous pyrogen but not that caused by LTB4, PAF and rIL-8. 132 96

alpha-Melanocyte-stimulating hormone (alpha-MSH1-13), a peptide derived from proopiomelanocortin, has remarkable anti-inflammatory and antipyretic activities. This peptide and a tripeptide that forms the COOH-terminal portion of the molecule (alpha-MSH11-13; Lys Pro Val) inhibit inflammation when given centrally or peripherally. Because of the similarity in their actions, the tripeptide has been presumed to be the amino acid message sequence underlying the effects of alpha-MSH1-13. To test the possibility that the two peptides occupy the same receptors, competitive binding experiments were performed with B16 mouse melanoma cells that are known to have alpha-MSH1-13 receptors. In these experiments, alpha-MSH11-13 did not inhibit binding of a radiolabelled alpha-MSH1-13 analog. This finding suggests that alpha-MSH1-13 and alpha-MSH11-13 exert their anti-inflammatory/antipyretic/anticytokine effects via stimulation of separate receptors. Because alpha-MSH inhibits the effects of several cytokines including inflammation caused by interleukin (IL)-6 and IL-8, the capacity of these cytokines to compete for alpha-MSH binding sites was tested. There was no evidence that these proinflammatory cytokines bind to alpha-MSH receptors on murine melanoma cells. Although further tests with host cells involved in inflammation are required, the latter result is the first evidence that the mechanism of anticytokine action of alpha-MSH does not depend upon peptide/cytokine competition for binding sites.
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PMID:Binding of anti-inflammatory alpha-melanocyte-stimulating-hormone peptides and proinflammatory cytokines to receptors on melanoma cells. 748 22

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) has potent antipyretic and antiinflammatory properties. When administered systemically, the naturally occurring molecule and its COOH-terminal tripeptide sequence inhibit inflammation induced by peripherally applied irritants and intradermal injections of mediators of inflammation such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha). We recently found that alpha-MSH can act solely within the brain to inhibit inflammation caused by a general irritant applied to the skin. This activity appears to be shared with salicylate drugs and the combined observations suggest the existence of descending neurogenic antiinflammatory signals capable of modulating inflammation in peripheral tissues. To improve our knowledge of the scope of this action of the peptide, alpha-MSH was injected into the cerebral ventricles (i.c.v.) of mice that had received intradermal injections in the ear of mediators of inflammation: IL-1 beta, IL-8, leukotriene B4, and platelet-activating factor. The centrally administered peptide inhibited the actions of all of these proinflammatory agents as determined from comparisons with measures of ear edema over time in control animals; this indicates that the central peptide can alter inflammation induced in the periphery by major mediators of inflammation. In tests confined to IL-1 beta, central administration of alpha-MSH(11-13) was also effective. These findings support the concept of a descending neurogenic antiinflammatory influence promoted by an action of alpha-MSH within the brain, an inhibitory influence that is not restricted to modulation of just one or a limited set of the mediators of inflammation.
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PMID:Central neurogenic antiinflammatory action of alpha-MSH: modulation of peripheral inflammation induced by cytokines and other mediators of inflammation. 812 2

Alpha-Melanocyte-stimulating hormone (MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. We showed previously that alpha-MSH inhibits nitric oxide (NO) production in cultured macro-phages. To determine how alpha-MSH acts in vivo, we induced acute hepatic inflammation by administering endotoxin (LPS) to mice pretreated with Corynebacterium parvum, alpha-MSH prevented liver inflammation even when given 30 min after LPS administration. To determine the mechanisms of action of alpha-MSH, we tested its influence on NO, infiltrating inflammatory cells, cytokines, and chemokines. Alpha-MSH inhibited systemic NO production, hepatic neutrophil infiltration, and increased hepatic mRNA abundance for TNF alpha, and the neutrophil and monocyte chemokines (KC/IL-8 and MCP-1). We conclude that alpha-MSH prevents LPS-induced hepatic inflammation by inhibiting production of chemoattractant chemokines which then modulate infiltration of inflammatory cells. Thus, alpha-MSH has an effect very early in the inflammatory cascade.
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PMID:Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation. 862 92

We have developed an enzyme-linked immunosorbent assay (ELISA) for the sequential analysis of multiple cytokines in limited volumes of biological fluids, including gingival crevicular fluid (GCF) and fibroblast culture supernatants (CS). GCF and CS samples were assayed for multiple cytokines, including IL-1 beta, IL-6, IL-8, GM-CSF and IFN gamma. Immulon 3 microplates were coated with a monoclonal antibody, and a rabbit polyclonal antibody was used to detect the cytokine of interest. Biological samples (200 microL) were added to an anti-IL-1 beta-coated plate and incubated, and 175 microL of each sample were replicate transferred to an anti-IFN gamma-coated plate containing 25 microL/well of diluent. This was repeated in an identical fashion with sequential replicate transfers to an anti-IL-8-coated and finally an anti-IL-6-coated plate. The cytokine standard was a pooled combination of the recombinant human cytokines that were included in the sequence. The plates were developed using an alkaline phosphatase-conjugated goat anti-rabbit IgG and NPP as the substrate. Individual ELISAs ranged in sensitivity from 30 to 2 pg/0.2 mL, with cross-reactivity between these cytokines of < 1%. Additionally, when the same samples were tested in the sequence ELISA vs. the individual ELISA, there was > 85% correlation between the two assays.
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PMID:Sequential ELISA for cytokine levels in limited volumes of biological fluids. 887 92

Pro-opiomelanocortin (POMC)-derived peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) recently have been recognized as mediators with potent immunomodulating and anti-inflammatory properties. Their effects are mediated via different protein G-coupled melanocortin (MC) receptors that are capable to bind one or more POMC-derived peptides. Among these receptors, MC-1 is specific for alpha-MSH and adrenocorticotropin. The purpose of the present study was to investigate whether MC receptors are expressed on normal human dermal microvascular endothelial cells (HDMEC) as well as transformed human dermal microvascular endothelial cells (HMEC-1). Using semiquantitative reverse transcriptase-PCR and MC receptor-specific primers, both HDMEC and HMEC-1 were found to express MC-1 constitutively. In addition, MC-1 expression was increased upon stimulation with IL-1beta or alpha-MSH itself. Other known MC receptors were neither detectable in unstimulated nor in IL-1beta- or alpha-MSH-stimulated cells. The binding of alpha-MSH by HMEC-1 was specific and saturable as demonstrated by competitive and saturation-binding studies with 125I-labeled alpha-MSH (Kd: 1.1 nM). To evaluate the physiologic relevance of MC-1 expression, HMEC-1 were treated with various concentrations of alpha-MSH (10(-15)-10(-6) M) and were investigated for their cytokine-producing capacity. Alpha-MSH (10(-10)-10(-8) M) significantly up-regulated IL-8 release and mRNA expression by HMEC-1. In contrast, the production of IL-1 or IL-6 by HMEC-1 was not affected upon treatment with alpha-MSH. These data provide first evidence that HDMEC express functional MC receptors. Therefore, alpha-MSH, which is released in the skin during cutaneous inflammation via inducing chemokines may represent an important signal required for leukocyte-endothelial cell interaction.
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PMID:Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocyte-stimulating hormone. 925 58

Chemokines consist of a family of 8-16-kDa cytokines that are generated very early in a wide variety of inflammatory responses and attract leukocytes to local sites. At nanomolar concentrations chemokines initiate signal transduction and activate leukocytes through seven transmembrane receptors (STM), but higher micromolar doses result in homologous desensitizing effects. On the basis of reports that opiates have anti-inflammatory effects and also use STM, we have investigated the possibility that they may cross-desensitize the response of leukocytes to chemokines. We have confirmed previous observations that met-enkephalin (MET) is chemotactic for human peripheral blood monocytes. Furthermore, we observed that preincubation of monocytes or neutrophils with MET or morphine prevented their subsequent chemotaxis in response to chemokines (MIP1 alpha or IL-8). However, MET did not inhibit the chemotactic response of PMN to NAP-2, a homologous chemokine that is less potent than IL-8 but cannot be desensitized. The inhibitory effect of opiates on chemokine-induced chemotaxis was antagonized by naloxone. Since MIP-1 alpha and IL-8, unlike NAP-2, have the capacity to desensitize leukocytes, it is possible that opiates, by desensitizing some chemokine responses, can suppress inflammatory reactions.
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PMID:Opiate inhibition of chemokine-induced chemotaxis. 962 32

An intact chemotactic response is vital for leukocyte trafficking and host defense. Opiates are known to exert a number of immunomodulating effects in vitro and in vivo, and we sought to determine whether they were capable of inhibiting chemokine-induced directional migration of human leukocytes, and if so, to ascertain the mechanism involved. The endogenous opioid met-enkephalin induced monocyte chemotaxis in a pertussis toxin-sensitive manner. Met-enkephalin, as well as morphine, inhibited IL-8-induced chemotaxis of human neutrophils and macrophage inflammatory protein (MIP)-1alpha, regulated upon activation, normal T expressed and secreted (RANTES), and monocyte chemoattractant protein 1, but not MIP-1beta-induced chemotaxis of human monocytes. This inhibition of chemotaxis was mediated by delta and micro but not kappa G protein-coupled opiate receptors. Calcium flux induced by chemokines was unaffected by met-enkephalin pretreatment. Unlike other opiate-induced changes in leukocyte function, the inhibition of chemotaxis was not mediated by nitric oxide. Opiates induced phosphorylation of the chemokine receptors CXCR1 and CXCR2, but neither induced internalization of chemokine receptors nor perturbed chemokine binding. Thus, inhibition of chemokine-induced chemotaxis by opiates is due to heterologous desensitization through phosphorylation of chemokine receptors. This may contribute to the defects in host defense seen with opiate abuse and has important implications for immunomodulation induced by several endogenous neuropeptides which act through G protein-coupled receptors.
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PMID:Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. 967 44

We show that infection of primary monocyte-derived macrophages (MDMs) and blood lymphocytes (PBLs) by human immunodeficiency virus type 1 (HIV-1) R5 strains, but not that of PBLs by X4 strain HIV-1LAI, is inhibited by beta-chemokines RANTES and MIP-1alpha. A biotinylated disulfide-bridged peptide mimicking the complete loop of clade B consensus V3 domain of gp120 (V3Cs), but not a biotinylated V3LAI peptide or a control beta-endorphin peptide of approximately the same molecular weight (MW), was found to bind specifically to MDM membrane proteins, in particular two proteins of 42 and 62 kDa migrating as sharp bands after electroblotting onto Immobilon, and this was specifically inhibited by anti-V3 antibodies. When biotinylated V3Cs was incubated with intact MDMs, which were then washed and lysed, and the resulting material was incubated with streptavidin-agarose beads and electroblotted onto Immobilon, fresh V3Cs also bound to proteins of the same molecular weight recovered in the V3Cs-interacting material. This binding was inhibited by anti-V3 antibodies, and no binding occurred with the control peptides. V3Cs also bound to soluble recombinant CD4, and CD4 monoclonal antibody Q4120 specifically recognized the V3Cs-interacting 62-kDa protein, which should thus correspond to CD4. Recombinant radiolabeled RANTES, MIP-1alpha, and MIP-1beta, but not IL-8, also bound to a 42-kDa protein on the membrane of MDMs as well as to the V3Cs-interacting 42-kDa protein, and excess unlabeled V3Cs inhibited such binding. This protein was also recognized by antibodies to CCR5, the RANTES/MIP-1alpha/MIP-1beta receptor. These data show that V3Cs binds to MDM membrane proteins that comprise CD4 and CCR5, and that multimolecular complexes involving at least gp120 V3, CD4, and CCR5 are formed on the surface of MDMs as part of V3-mediated postbinding events occurring during HIV-1 infection.
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PMID:Interaction of human immunodeficiency virus type 1 envelope glycoprotein V3 loop with CCR5 and CD4 at the membrane of human primary macrophages. 987 Mar 13

Modulation of tumour cell growth by tumour-infiltrating leucocytes is of high importance for the biological behaviour of malignant neoplasms. In melanoma, tumour-associated macrophages (TAM) and tumour-infiltrating lymphocytes (TIL) are of particular interest as inhibitors or enhancers of cell growth. Recruitment of leucocytes from the peripheral blood into the tumour site is mediated predominantly by chemotaxins, particularly by the group of chemokines. The aim of this study was to identify peptides released by human melanoma cells with monocyte chemotactic properties. To assure the presence of biologically active mediators, biochemical purification and biological characterization of peptides was based on a detection system dependent on bioactive, monocyte chemotactic activity in vitro. Cell culture supernatants of melanoma cells were fractioned by heparin-sepharose followed by preparative reversed-phase HPLC steps to enrich monocyte chemotactic activity in one single band on a sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) gel. These purified fractions were shown to react with RANTES-specific antibodies in an enzyme-linked immunosorbent assay (ELISA) as well as in Western blot analysis. Amino acid sequencing of the N-terminal protein fragment confirmed 100% homology to the RANTES protein. Further analysis showed that four out of eight melanoma cell lines constitutively expressed and secreted the beta-chemokine RANTES as detected by ELISA. The amount of RANTES protein secreted (up to 50 ng ml(-1)) was about 5-50 times higher than interleukin 8 (IL-8), determined in the same supernatant samples. Tumour necrosis factor alpha, (TNF-alpha), not, however, IL-2, interferon-gamma (IFN-gamma), or (alpha-melanocyte-stimulating hormone (alpha-MSH) was able to up-regulate RANTES and interleukin 8 secretion. Furthermore, higher levels of RANTES secretion in vitro were associated with increased tumour formation upon s.c. injection of six human melanoma cell lines in nude mice. Our data provide evidence that a subset of melanoma cells express mRNA and secrete RANTES protein which may be partly responsible for the recruitment of monocytes, T-cells and dendritic cells into the tumours. However, transplantation experiments in nude mice suggest that effects of RANTES may also benefit tumour progression. Further studies are needed to dissect the underlying mechanisms.
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PMID:The chemokine RANTES is secreted by human melanoma cells and is associated with enhanced tumour formation in nude mice. 1009 31


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