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)

Previous work in our laboratory has shown that both mu- and kappa-opioid agonists exhibit immunosuppressive activity for antibody responses in vitro. Our earlier work has suggested that both accessory cells and T cells may be altered following treatment with the kappa-opioid agonist U50,488H. We intend to further determine the identity of the immune cell population(s) which are affected by opioid treatment, and to determine the nature of the opioid receptor type expressed on these cells. In this study, non- elicited peritoneal macrophages were treated simultaneously with the kappa-agonist U50,488H and lipopolysaccharide (LPS), and the levels of the cytokines interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha were determined. The results show that U50,488H had a suppressive effect on the production of TNF-alpha and IL-1 at concentrations as low as 1 nM, while IL-6 was suppressed at concentrations as low as 10 nM. Additional experiments utilizing the opiate antagonist naloxone and the kappa-selective antagonist norbinaltorphimine (norBNI) were performed in order to further characterize the opioid receptor involved in the cytokine suppression produced by treatment with U50,488H. Results showed that naloxone was able to partially block U50,488H suppression while norBNI was able to completely reverse the suppression of IL-6 production. These results suggest that macrophage/monocyte function is significantly modulated following activation of the kappa-opioid receptor.
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PMID:Inhibition of primary murine macrophage cytokine production in vitro following treatment with the kappa-opioid agonist U50,488H. 859 93

Chronic use of morphine affects the immune system and predisposes an individual to opportunistic infections. Macrophages play an important role in conferring a first line of defense against invading pathogens. Understanding the mechanisms by which morphine affects the functioning of macrophages would have significant therapeutic benefit in treatment against infections such as HIV and AIDS related syndromes. Two of the major cytokines secreted by activated macrophages are Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). Our studies show that morphine differentially modulates lipopolysaccharide (LPS) induced expression of IL-6 and TNF-alpha. Nanomolar concentrations of morphine synergize with LPS and augment the secretion of both IL-6 and TNF-alpha. However, at micromolar concentrations morphine inhibits LPS induced synthesis of IL-6 and TNF-alpha. Expression of both these cytokine genes is dependent on the activation of a transcription factor, NF kappa B. Interestingly, morphine treatment also modulated the activation of NF kappa B by LPS. Pretreatment with a low dose of morphine (nanomolar) resulted in an increase in NF kappa B activation. In contrast pretreatment with a high dose of morphine (micromolar) led to a significant decrease in NF kappa B activation. Furthermore unlike the augmentation which was naloxone reversible, the inhibition of NF kappa B by morphine was not reversed by naloxone, suggesting the involvement of a nonclassical opioid receptor.
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PMID:Morphine modulates NF kappa B activation in macrophages. 957 Nov 61

In this paper, we describe that met-enkephalin and/or enkephalin-containing intermediary peptides of the prohormone pro-enkephalin A are produced and secreted by human peripheral blood T cells and monocytes. The peptides are produced after stimulation with the mitogenic monoclonal antibodies anti-CD2.1/2.2 and anti-CD28. In monocytes, enkephalin synthesis was induced by stimulation with lipopolysaccharide. We demonstrate here that these immune cell-derived enkephalins play an important regulatory role in the immune response. By using an anti-sense oligonucleotide strategy we could block the production of enkephalins. Blockade of the production of met-enkephalin and enkephalin-containing intermediary peptides resulted in enhancement of the proliferative T cell response and inhibition of monocyte IL-6 secretion. In vitro reconstitution of the anti-sense treated cultures with synthetic met-enkephalin or the delta-type specific opioid receptor agonist deltorphin could reverse inhibition of monocyte IL-6 production, suggesting that endogenous enkephalins act via membrane opioid receptors. In contrast, addition of met-enkephalin or deltorphin to the anti-sense treated T cell cultures did not have any effect on T cell proliferation.
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PMID:Role of endogenous pro-enkephalin A-derived peptides in human T cell proliferation and monocyte IL-6 production. 960 Jul 8

We investigated the effects of (+)-4-[(alpha R)-alpha-((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC 80), a nonpeptidic delta-opioid receptor-selective agonist, on rat leukocyte functions. Intracerebroventricular injection of SNC 80 (20 nmol) in Fischer 344N male rats did not affect splenic natural killer cell activity compared with intracerebroventricular saline-injected controls. SNC 80 also had no effect on concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic and thymic lymphocyte proliferation in most experiments. In some experiments, however, SNC 80 significantly (P < .01) caused a 41 to 93% increase of concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic lymphocyte proliferation compared to controls. Additionally, SNC 80 did not significantly affect splenic T cell or natural killer cell populations as measured by the expression of T cell receptoralphabeta, and T helper (CD4), T suppressor/cytotoxic (CD8) and natural killer cell surface markers. Finally, SNC 80 did not affect interferon-gamma- or lipopolysaccharide (LPS)-induced splenic nitric oxide, and LPS-induced tumor necrosis factor-alpha production by splenic macrophages. These results suggest that SNC 80 could be useful in the treatment of pain without suppressing immune function. However, the potential immunoenhancing properties of SNC 80 may be also valuable in immunocompromised individuals.
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PMID:Rat natural killer cell, T cell and macrophage functions after intracerebroventricular injection of SNC 80. 969 52

In the present study, we tested the hypothesis that lipopolysaccharide (LPS)-induced expression of nitric oxide synthase (iNOS) by splenocytes is modulated through the activation of endogenous opioids in the central nervous system. The initial studies determined the parameters of LPS-induced expression of iNOS by splenocytes. Rats were injected with LPS at doses of 0, 1, 10, 100, and 1000 microg/kg, and measures of both iNOS mRNA and protein showed a dose-dependent increase in expression. In a time course study, rats received 100 microg/kg LPS and were killed at 0, 2, 4, 8, and 16 h postinjection. Both iNOS mRNA and protein expression was detectable at the 2-h time point, with peak expression occurring at 8 h. To evaluate the involvement of endogenous opioids, the opioid receptor antagonist naltrexone was administered at 0, 0.1, 1, or 10 mg/kg s.c. in combination with LPS (100 microg/kg), with a second injection of naltrexone at the same dose 4 h after the injection of LPS. Naltrexone induced a pronounced dose-dependent reduction in iNOS mRNA and protein expression by splenocytes. The modulation of iNOS expression occurs via central opioid receptors as intracerebroventricular administration but not peripheral administration of N-methylnaltrexone, the quaternary form of naltrexone that does not readily cross the blood-brain barrier, reduced the expression of iNOS. For all of the manipulations, nitrite/nitrate levels in the plasma showed effects similar to those for iNOS mRNA and protein. Collectively, these findings indicate that central opioid receptors are involved in the in vivo regulation of splenic nitric oxide production.
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PMID:Endogenous opioids regulate the expression of inducible nitric oxide synthase by splenocytes. 991 51

The effects of methionine-enkephalin and the selective agonists of mu-, delta- and kappa-opioid receptor subtypes [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, [D-Pen(2,5)]enkephalin U-50488 on the production of nitrite by activated peritoneal murine macrophages were studied. Macrophages were activated with interferon-gamma plus lipopolysaccharide in the presence or absence of graded concentrations of opioids. Methionine-enkephalin and mu-; delta- and kappa-agonists combined with interferon-gamma plus lipopolysaccharide caused an increase in nitrite release from cultured macrophages. Only 10 mM U-50488 led to a decrease in nitrite release from interferon-gamma and LPS-stimulated macrophages. This effect was not produced in a naloxone-sensitive manner. The opioids added to the fresh culture 8 h after the stimulation of macrophages by interferon-gamma plus lipopolysaccharide--when an inducible form of nitric oxide synthase activity is presumably expressed--did not alter the rate of nitrite production. This suggests that the effect of opioids on nitric oxide synthase is produced at the transcriptional level. The opioid receptor antagonist naloxone reduced the stimulatory effect of opioids on nitrite production by stimulated macrophages. Opioids added to the culture of resting macrophages did not change nitrite release from macrophages which were later induced with interferon-gamma plus lipopolysaccharide. The results of this study suggest that methionine-enkephalin can modulate the immune response by controlling, via opioid receptors, the production of nitric oxide.
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PMID:Augmenting effect of opioids on nitrite production by stimulated murine macrophages. 1018 65

Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) administration induce hypophagia in rodents. Both IL-1 and LPS are known to activate cerebral norepinephrine and serotonin metabolism, and IL-1 affects that of acetylcholine and histamine. Each of these neurotransmitters has been implicated in feeding behavior. Therefore, the ability of specific antagonists of the above neurotransmitter systems to counteract feeding responses to peripherally injected mIL-1beta and LPS was studied. Feeding was assessed in nondeprived mice by measuring the intake of sweetened milk in a 30-min period, as well as daily food pellet intake. LPS and mIL-1beta reliably reduced milk intake, and often reduced food pellet intake and body weight. Treatment of the mice with peripherally administered alpha-adrenergic (phentolamine or prazosin) or 3-adrenergic antagonists (propranolol), either alone or in combination, did not significantly alter the hypophagic responses to mIL-1beta or LPS. Mice in which cerebral norepinephrine was depleted with DSP-4 or 6-hydroxydopamine also displayed the usual hypophagia in response to mIL-1beta and LPS. The hypophagic responses to mIL-1beta and LPS were not affected by the histaminergic antagonists, pyrilamine (H1), cimetidine (H2), thioperamide (H3), or the histamine-depleting agent, alpha-fluoromethylhistidine, nor by the muscarinic cholinergic antagonist, scopolamine. The responses to mIL-l1 were also unaffected by the dopamine receptor antagonist, haloperidol, the opioid receptor antagonist, naloxone, and the NO synthase inhibitor, L-NAME. These results suggest that adrenergic, dopaminergic, histaminergic, cholinergic, opioid or nitric oxide systems are not essential for the hypophagia induced by IL-1, and that multiple redundant pathways may be involved in illness-related hypophagia.
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PMID:Endotoxin- and interleukin-1-induced hypophagia are not affected by adrenergic, dopaminergic, histaminergic, or muscarinic antagonists. 1046 92

The use of heroin (diacetylmorphine) is associated with a high incidence of infectious disease, and the immunologic alterations responsible for heroin-induced changes in resistance to infection have not been well characterized. The present study tests the hypothesis that expression of inducible nitric oxide synthase (iNOS) is modulated by the administration of heroin. The initial study using rats showed that heroin administration (0, 0.01, 0.1, or 1.0 mg/kg s.c.) results in a pronounced reduction in lipopolysaccharide (LPS)-induced expression of iNOS mRNA in spleen, lung, and liver tissue as measured by RT-PCR. Heroin also produced a reduction in the level of plasma nitrite/nitrate, the more stable end-product of nitric oxide degradation. In a subsequent study, administration of the opioid receptor antagonist, naltrexone (0.1 mg/kg) prior to the injection of heroin (1.0 mg/kg) blocked the heroin-induced reduction of iNOS expression and plasma nitrite/nitrate levels indicating that the effect is mediated via the opioid-receptor. This study provides the first evidence that heroin induces an alteration of iNOS expression, and suggests that a reduction in nitric oxide production may be involved in the increased incidence of infectious diseases amongst heroin users.
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PMID:Heroin modulates the expression of inducible nitric oxide synthase. 1074 99

Degeneration of dopaminergicrgic neurons in the substantia nigra of the brain is a hallmark of Parkinson's disease and inflammation and oxidative stress are closely associated with the pathogenesis of degenerative neurological disorders. Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS)-activated microglia, resident immune cells of the brain, to release proinflammatory and neurotoxic factors tumor necrosis factor-alpha, interleukin-1beta, nitric oxide, and superoxide and subsequently caused damage to midbrain neurons, including dopaminergic neurons. The LPS-induced degeneration of the midbrain neurons was significantly reduced by cotreatment with naloxone, an opioid receptor antagonist. This study focused on understanding the mechanism of action for the protective effect of naloxone on dopaminergic neurons because of relevance to Parkinson's disease. Both naloxone and its opioid receptor inactive stereoisomer (+)-naloxone protected the dopaminergic neurons with equal potency. Naloxone inhibited LPS-induced activation of microglia and release of proinflammatory factors, and inhibition of microglia generation of superoxide free radical best correlated with the neuroprotective effect of naloxone isomers. To further delineate the site of action, naloxone was found to partially inhibit the binding of [(3)H]LPS to cell membranes, whereas it failed to prevent damage to dopaminergic neurons by peroxynitrite, a product of nitric oxide and superoxide. These results suggest that naloxone at least in part interferes with the binding of LPS to cell membranes to inhibit microglia activation and protect dopaminergic neurons as well as other neurons in the midbrain cultures from inflammatory damage.
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PMID:Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. 1077 35

Microglia as the first line of defensive cells in the brain produce free radicals including superoxide and nitric oxide (NO), contributing to neurodegeneration. An opioid receptor antagonist, naloxone, has been considered pharmacologically beneficial to endotoxin shock, experimental cerebral ischemia, and spinal cord injury. However, the mechanisms underlying these beneficial effects of naloxone are still not clear. This study explores the effects of naloxone on the production of superoxide and NO by the murine microglial cell line, BV2, stimulated with lipopolysaccharide (LPS) as measured by electron paramagnetic resonance (EPR). The production of superoxide triggered by phobol-12-myristate-13-acetate (PMA) resulted in superoxide dismutase (SOD)-inhibitable, catalase-uninhibitable 5,5-dimethyl-1-pyrroline N-oxide (DMPO) hydroxyl radical adduct formation. LPS enhanced the production of superoxide and triggered the formation of non-heme iron-nitrosyl complex. Cells pre-treated with naloxone showed significant reduction of superoxide production by 35%. However, it could not significantly reduce the formation of non-heme iron-nitrosyl complex and nitrite. Taken together, the results expand our understanding of the neuroprotective effects of naloxone as it decreases superoxide production by microglia.
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PMID:A novel effect of an opioid receptor antagonist, naloxone, on the production of reactive oxygen species by microglia: a study by electron paramagnetic resonance spectroscopy. 1078 26


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