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

Peripheral nervous system injury may be corrected by surgical repair, but in many cases this is not possible and will result in loss of motor and sensory function. Schwann cells provide many neurotrophic signals essential for axon regeneration and immediately after injury inflammatory cytokines are released necessary for Schwann cell de-differentiation. However, extended periods of inflammation after injury prevent Schwann cell proliferation, and therefore interventional approaches to enhance proliferation may in turn improve axon regeneration. We therefore investigated the ability of alpha-melanocyte stimulating hormone (alpha-MSH; a potent anti-inflammatory peptide) to inhibit the activation of the NF-kappaB transcription factor (required for inflammatory signalling) in cultured rat primary Schwann cells, stimulated with tumour necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma). Both cytokines activated NF-kappaB rapidly after 60 min incubation, observed as a translocation from the cytoplasm to the nucleus. alpha-MSH inhibited activation (i.e. inhibited nuclear translocation) in response to TNF-alpha or IFN-gamma by 81% and 100% respectively. The anti-inflammatory properties of this peptide may therefore have potential for treatment of peripheral nerve injury to improve the healing response.
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PMID:Alpha-MSH inhibits inflammatory signalling in Schwann cells. 1509 10

There is evidence that alpha-melanocyte-stimulating hormone (alpha-MSH) has immunomodulatory and anti-inflammatory actions within the brain. In this study, we tested whether these actions are due to inhibition of the synthesis of nitric oxide (NO) and prostaglandins induced by lipopolysaccharide (LPS). Since melanocortin subtype MC4 receptor has been detected in the hypothalamus, we investigated the effect of central administration of alpha-MSH and HS024 (a selective MC4 receptor antagonist) on the gene expression of inducible, neuronal and endothelial NO synthase (iNOS, nNOS and eNOS) and on cyclooxygenase (COX-1 and COX-2) expression in the mediobasal hypothalamus (MBH) of LPS-treated male Wistar rats. Peripheral administration of LPS (250 microg/rat, 3 h) induced iNOS and COX-2 gene expression in the MBH. This stimulatory effect was reduced by alpha-MSH (3 nmol/rat) injected 30 min before LPS. alpha-MSH and HS024 (1 nmol/rat) alone had no effect on iNOS and COX-2 expression. The action of alpha-MSH on LPS-induced iNOS and COX-2 mRNA levels was not observed in the presence of HS024, suggesting that MC4-R may be involved in the modulatory effect of alpha-MSH. None of these treatments produced any modifications in nNOS, eNOS and COX-1 expression in MBH. The increase in serum corticosterone levels induced by LPS was attenuated by alpha-MSH. Both LPS and alpha-MSH decreased serum LH and prolactin levels. HS024 failed to modify the inhibitory effects of LPS and alpha-MSH on prolactin release but reverted the effect of LPS on LH secretion, indicating that MC4-R activation may be involved in the effects of alpha-MSH on LH secretion in male rats. When we examined the in vitro effect of LPS (10 microg/ml) and LPS plus interferon-gamma (IFN-gamma, 100 ng/ml) on iNOS expression in MBH, an increase in iNOS mRNA levels was observed only in the presence of LPS + IFN-gamma. This stimulatory effect was attenuated in the presence of alpha-MSH (5 microM), which by itself had no effect. No changes were found in nNOS, eNOS, COX-1 or COX-2 expression. These results indicate that alpha-MSH reduces the induction of iNOS and COX-2 gene expression at the hypothalamic level during endotoxemia and suggest that endogenous alpha-MSH may exert an inhibitory tone on iNOS and COX-2 transcription via MC4 receptors acting as a local anti-inflammatory agent within the hypothalamus.
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PMID:Alpha-melanocyte-stimulating hormone through melanocortin-4 receptor inhibits nitric oxide synthase and cyclooxygenase expression in the hypothalamus of male rats. 1521 20

The responses of plasma cortisol and adrenocorticotropic hormone (ACTH) were examined to intravenous injection of recombinant bovine tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (INF-gamma) in Holstein cows. INF-gamma induced dose-dependent rises in the plasma levels of both cortisol and ACTH, while TNF-alpha induced comparable plasma cortisol responses with much smaller rises in plasma ACTH. The results suggest a direct stimulatory action of TNF-alpha on cortisol secretion from the adrenal gland in cattle.
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PMID:Adrenocortical responses to tumor necrosis factor-alpha and interferon-gamma in cattle. 1548 63

Proopiomelanocortin (POMC)-derived peptides and their receptors have been identified in many peripheral organs including the skin in which they exert a diversity of biological actions. We investigated the expression and potential role of the POMC system in human dermal papilla cells (DPCs), a specialized cutaneous mesenchymal cell type regulating hair follicle activity. In culture, these cells expressed POMC and displayed immunoreactivity for ACTH, alphaMSH, and beta-endorphin. Among the prohormone convertases (PCs) tested, only PC2, its chaperone 7B2, and furin convertase but not PC1 and paired basic amino acid cleaving enzyme 4 gene were detected. Human DPCs in vitro expressed both the melanocortin-1 receptor (MC-1R) and MC-4R, and immunoreactivity for these receptors was also present in cells of the human dermal papilla in situ. In contrast to the dermal papilla of agouti mice, agouti signaling protein, a natural and highly selective MC-1R and MC-4R antagonist, was undetectable in human DPCs. The MC-Rs detected in human DPCs were functionally active because alphaMSH increased intracellular cAMP and calcium. Preincubation of the cells with a synthetic peptide corresponding to the C-terminal domain of agouti signaling protein abrogated cAMP induction by alphaMSH. Furthermore, alphaMSH was capable of antagonizing the expression of intercellular adhesion molecule-1 induced by the proinflammatory cytokine interferon-gamma. Our data suggest a regulatory function of alphaMSH within the dermal papilla whose disruption may lead to deregulation of immune and inflammatory responses of the hair follicle, thereby possibly contributing to the development of inflammatory forms of alopecia.
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PMID:Detection of functionally active melanocortin receptors and evidence for an immunoregulatory activity of alpha-melanocyte-stimulating hormone in human dermal papilla cells. 1608 29

Senile plaques in the Alzheimer's disease (AD) are formed by aggregation of beta-amyloid (Abeta) peptide. Abeta peptide has been shown to activate microglia and stimulate their production of inflammatory factors, such as cytokines. In the AD brain, the continued presence of amyloid plaques may keep microglia persistently activated, leading to chronic inflammation in the CNS. It is well established that alpha-melanocyte-stimulating hormone (alpha-MSH) gives rise to anti-inflammatory and anti-pyretic effects. The biological activities of alpha-MSH are mediated by one or more of the melanocortin receptor (MCR) subtypes, i.e. MCR1 - MCR5. The aim of the present study was to determine the effect of alpha-MSH alone and on Abeta-activated microglial cells with regard to the secretion of inflammatory cytokines, such as interleukin-6 (IL-6), and to determine which receptor subtype mediates the effects of alpha-MSH. The human microglial cell line, CHME3, was incubated for 24 h with freshly dissolved Abeta(1-40), interferon-gamma (IFN-gamma) and/or alpha-MSH. Freshly dissolved Abeta(1-40) (5-60 microM) resulted in a dose-dependent decrease in cell viability, along with a dose-dependent increase in IL-6 release. Neither IFN-gamma nor alpha-MSH affected the Abeta-induced secretion of IL-6, but resulted in a dose-dependent increase in basal IL-6 release. Agouti, the endogenous antagonist of MCR1 and 4, further increased the alpha-MSH-induced secretion of IL-6. RT-PCR showed the expression of MCR1, MCR3, MCR4 and MCR5 mRNA. The combined data suggest that the effect of alpha-MSH in increasing IL-6 release from the human microglial cell line is mediated by MCR3 or MCR5.
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PMID:Cytokine production by a human microglial cell line: effects of beta-amyloid and alpha-melanocyte-stimulating hormone. 1637 21

There is increasing evidence that stress plays a role in the pathophysiology of chronic intestinal disorders, but the mechanisms remain unclear. Previous studies in rats have revealed that stress decreases gut barrier function and allows excessive uptake of luminal material. Here, we investigated whether chronic psychological stress acts to induce sensitization of intestinal tissues to oral antigens. Rats were subjected to 1 hour per day of water avoidance stress or sham stress daily for 10 days, and horseradish peroxidase (HRP) was delivered by gavage on day 5. Studies to determine sensitization were conducted on day 20. All stressed rats developed HRP-specific IgE antibodies, antigen-induced intestinal secretion, and increased numbers of inflammatory cells in gut mucosa. Luminal HRP was absorbed more readily by enterocytes of stressed animals. In addition, stressed rats had increased expression of interleukin-4 and decreased expression of interferon-gamma in gut mucosa, a cytokine profile that is typical of allergic conditions. Treatment of stressed rats with an antagonist to corticotropin-releasing hormone (previously shown to inhibit stress-enhanced gut permeability) eliminated the manifestations of intestinal hypersensitivity. Our results indicate that the presence of oral antigen during chronic psychological stress alters the immune response (to sensitization rather than oral tolerance) and causes subsequent antigen-induced gut pathophysiology.
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PMID:Chronic psychological stress in rats induces intestinal sensitization to luminal antigens. 1640 3

Alpha-MSH exerts an immunomodulatory action in the brain and may play a neuroprotective role acting through melanocortin 4 receptors (MC4Rs). In the present study, we show that MC4Rs are constitutively expressed in astrocytes as determined by immunocytochemistry, RT-PCR, and Western blot analysis. alpha-MSH (5 microm) reduced the nitric oxide production and the expression of inducible nitric oxide synthase (iNOS) induced by bacterial lipopolysaccharide (LPS, 1 microg/ml) plus interferon-gamma (IFN-gamma, 50 ng/ml) in cultured astrocytes after 24 h. alpha-MSH also attenuated the stimulatory effect of LPS/IFN-gamma on prostaglandin E(2) release and cyclooxygenase-2 (COX-2) expression. Treatment with HS024, a selective MC4R antagonist, blocked the antiinflammatory effects of alpha-MSH, suggesting a MC4R-mediated mechanism in the action of this melanocortin. In astrocytes, LPS/IFN-gamma treatment reduced cell viability, increased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells and activated caspase-3. alpha-MSH prevented these apoptotic events, and this cytoprotective effect was abolished by HS024. LPS/IFN-gamma decreased Bcl-2, whereas it increased Bax protein expression in astrocytes, thus increasing the Bax/Bcl-2 ratio. Alpha-MSH produced a shift in Bax/Bcl-2 ratio toward astrocyte survival because it increased Bcl-2 expression and also prevented the effect of LPS/IFN-gamma on Bax and Bcl-2 expression. In summary, these findings suggest that alpha-MSH, through MC4R activation, attenuates LPS/IFN-gamma-induced inflammation by decreasing iNOS and COX-2 expression and prevents LPS/IFN-gamma-induced apoptosis of astrocytes by modulating the expression of proteins of the Bcl-2 family.
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PMID:Activation of melanocortin 4 receptors reduces the inflammatory response and prevents apoptosis induced by lipopolysaccharide and interferon-gamma in astrocytes. 1759 27

Superantigens (SAgs) activate the immune system by stimulating massive proliferation of T cells in a major histocompatibility complex (MHC)-dependent manner. This excessive increase in T cells results in the release of cytokines such as interleukin-2 (IL-2), interferon-gamma (IFNgamma), and tumor necrosis factor-alpha (TNFa). As an adaptive feedback mechanism, SAgs can also activate the hypothalamic pituitary adrenal (HPA) axis by stimulating the release of corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the anterior pituitary, and ultimately corticosterone (CORT) from the adrenal gland. Additionally, SAg exposure modifies behavior, although it has not been shown to induce malaise or decrease mobility. Some behavioral consequences include increased gustatory neophobia, neophobia to inanimate non-gustatory objects, and heightened anxiety. Cytokines such as TNFa have been shown to mediate some of these behavioral consequences as well as the endocrine and neurobiological effects of SAg exposure. The particular behavioral repertoire and cytokine profiles observed are in some cases unique to SAgs, as compared to other immune challenges such as lipopolysaccharide (LPS). Therefore, SAgs serve as a useful model to understand the behavioral, endocrine, and neurobiological effects of a T cell driven immune response.
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PMID:Impact of superantigenic molecules on central nervous system function. 1927 59

Recent studies in psychoneuroimmunology have indicated that proinflammatory cytokines cause several diseases and behaviors that overlap symptomatically with depression. It is known that the endogenous opioid peptide beta-endorphin regulates proinflammatory cytokine secretion from peripheral immune cells via mu-opioid receptor-dependent mechanisms. Therefore, it is possible that the functional polymorphism of the mu-opioid receptor gene (OPRM1, SNP: A118G) influences peripheral circulating proinflammatory cytokine levels and the health-related quality of life (QOL) even in healthy populations. In this study, we compared the serum concentrations of several proinflammatory cytokines (interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma)) and the health-related QOL between OPRM1 genotypes. Interestingly, serum concentrations of IL-6, TNF-alpha, and IFN-gamma were significantly lower and the general health score was significantly higher in carriers of the G allele, who show a strong binding of beta-endorphin to the mu-opioid receptor as compared to individuals without the G allele. Correlation analysis indicated that the general health score was negatively correlated with the IL-6 serum concentration. These results suggest that the sensitive endogenous opioid system in carriers of the G allele may suppress proinflammatory cytokine secretion from peripheral immune cells; consequently, it may influence the health perception.
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PMID:Association of polymorphism in the human mu-opioid receptor OPRM1 gene with proinflammatory cytokine levels and health perception. 1934 91

In order to characterize a wide spectrum of leukocyte functions with clinically applicable procedures, 0.06 ml each of heparinized whole blood was stimulated in triplicate for 4h with phytohemagglutinin (T cell stimulator), heat aggregated IgG (IgG Fc receptor stimulator), lipopolysaccharide (toll-like receptor (TLR)-4 stimulator), zymosan (TLR-2 stimulator), monoclonal antibody against T-cell receptor alpha/beta chain, recombinant interleukin-2, and solvent controls, then 32 different leukocyte function-associated mRNAs were quantified by the method reported previously (Mitsuhashi et al. Clin. Chem. 2006). Two control genes (beta-actin, beta-2-microglobulin) were not affected by these stimulations, whereas the induction of CCL chemokines-2, 4, 8, 20, CXCL chemokines-3, 10, interleukin (IL)-8 (markers of leukocyte accumulation/recruit), granzyme B, perforin 1, tumor necrosis factor superfamily-1, 2, 5, 14, 15, CD16 (markers of cell killing), IL10, transforming growth factor beta 1 (humoral factors of immune suppression), forkhead box P3, CD25, arginase (cellular markers of immune suppression), IL2, IL4, interferon-gamma, IL17 (markers of various subsets of T helper cells), granulocyte-macrophage colony-stimulating factor (marker of antigen presenting cells), immunoglobulin heavy locus (marker of B-cells), vascular endothelial growth factor (marker of angiogenesis), pro-opiomelanocortin (marker of local pain), and CD11a mRNA (marker of leukocyte adherence to endothelium) were identified by these stimulations. The blood volume in this assay was 1.44 ml, and 4 h' incubation in whole blood was physiological. Using triplicate aliquots of whole blood for both stimulant and solvent control, statistical conclusion was drawn for each stimulant for each mRNA. The method introduced in this study will be a new paradigm for clinical cellular immunology.
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PMID:Ex vivo simulation of leukocyte function: stimulation of specific subset of leukocytes in whole blood followed by the measurement of function-associated mRNAs. 2095 4


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