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)

Here we investigate the effects of the dihydropyridine-type antagonists of calcium channels nitrendipine, nimodipine, nisoldipine and the calcium channel agonist BAY K 8644 on the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in J774.2 macrophages cultured in vitro. Pretreatment of J774.2 cells with these dihydropyridines (10(-8) -3 x 10(-6) M for 30 min) dose-dependently inhibited the LPS-stimulated (1 microgram/ml, 24 h) nitrite formation. For instance, at 10(-6) M, the inhibition was 59 +/- 3% for nitrendipine; 47 +/- 5% for nimodipine and 42 +/- 3% for nisoldipine (n = 9; p < 0.05). BAY K 8644 caused a moderate, but significant inhibition of nitrite accumulation (by 16 +/- 3% at 10(-7) M, n = 9; p < 0.05). The inhibition of LPS-stimulated nitrite accumulation produced by nitrendipine, nimodipine, and BAY K 8644 was significantly smaller when they were applied 2 or 4 h after LPS, indicating that these agents inhibit the induction, but not the activity of the induced NOS. At concentrations which caused a significant inhibition of the LPS-stimulated nitrite accumulation, the dihydropyridine calcium channel modulators did not inhibit mitochondrial respiration. Thus, dihydropyridine calcium channel modulators (antagonists and an agonist) inhibit the induction of the calcium-independent isoform of NOS produced by LPS in J774.2 macrophages. This effect is not related to the modulation of intracellular calcium levels.
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PMID:Dihydropyridine antagonists and agonists of calcium channels inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages. 769 80

The effects of the cytokine, interleukin-1 beta (IL-1 beta), and its receptor antagonist IL-1ra, were studied on long-term potentiation in the dentate gyrus of rat hippocampal slices. Field excitatory postsynaptic potentials were recorded extracellularly in the molecular region of the dentate gyrus in response to stimulation of the medial perforant path. Low frequency synaptic transmission was unaffected by IL-1 beta (1 ng/ml), but pre-treatment with IL-1 beta completely blocked induction of long-term potentiation. Co-application of IL-1 beta and IL-1ra (100 ng/ml) attenuated the inhibitory effect of IL-1 beta. In parallel with these findings, we demonstrate that IL-1 beta also inhibited 45Ca influx into the slices. The inhibitory effect of IL-1 beta on induction was mimicked by tumour necrosis factor (TNF; 4.5 ng/ml) and lipopolysaccharide (LPS; 10 micrograms/ml). These results indicate a modulatory role for cytokines in hippocampus and suggest that the inhibitory effect of IL-1 beta on long-term potentiation may relate to its inhibitory effect on calcium channel activity.
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PMID:Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. 874 36

Cytokines are released from activated cells during acute and chronic pathologic processes including infection and malignancy. These processes and immunotherapy with cytokines are frequently accompanied by feeding suppression. The intracerebroventricular (ICV) microinfusion of low doses of interleukin 1 beta (IL-1 beta) decreases short- and long-term food intake by reducing meal size and meal duration; high amounts also decrease meal frequency and prolong intermeal intervals. The ICV microinfusion of interferon (IFN) suppresses only short-term feeding by reducing meal size and meal duration; IL-8 suppresses short-term feeding by reducing meal size. Bacterial lipopolysaccharide also reduces meal size. IL-1 beta is significantly more potent than IFN, IL-8, and other cytokines. Evidence also shows that only a subset of cytokines released during pathologic processes participate in the regulation of feeding. These behavioral effects of cytokines are blocked by the appropriate receptor antagonists and monoclonal antibodies. Cytokines affect the hypothalamus and this may result in feeding suppression. IL-1 beta and IFN act directly and specifically on the glucose-sensitive neurons in the ventromedial hypothalamic nucleus (a "satiety" site) and the lateral hypothalamic area (a "hunger" site). Pathophysiologic concentrations of IL-1 beta and IL-2 in the cerebrospinal fluid inhibit the calcium channel current in neurons. It is essential to characterize the mechanisms by which cytokines induce feeding suppression to understand appetite suppression during disease and immunotherapy.
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PMID:Cytokines and feeding suppression: an integrative view from neurologic to molecular levels. 874 49

The proinflammatory cytokine, interleukin-1 (IL-1) is elevated in the Alzheimer's disease (AD) brain. Studies from our laboratory have demonstrated that beta-amyloid (A beta) 1-42, fibrillar A beta 1-40 and A beta 25-35 induce the release of IL-1 beta from activated THP-1 cells, a human monocyte cell line. A beta also is chemotactic for primary rodent microglia and peritoneal macrophages. We hypothesize that A beta is a chemokine and induces these responses by interaction with chemotactic receptors. If this is true, then these A beta-induced responses should be calcium-dependent and require activation of pertussis toxin-sensitive G-proteins. To test this hypothesis, THP-1 cells were grown in culture with lipopolysaccharide (LPS) and incubated with A beta 1-42 (5 muM) in the presence and absence of a calcium chelator, an inhibitor of intracellular calcium mobilization, a calcium channel blocker, or pertussis toxin, a bacterial endotoxin which uncouples G proteins from receptors by catalyzing the ADP ribosylation of cysteine near the carboxy-terminus of the alpha subunit. The media was collected and IL-1 beta present in the media was measured using an ELISA. Treatment of LPS-activated THP-1 cells with A beta 1-42 significantly elevated IL-1 beta released into the media as previously shown. Addition or ethylene glycol-bis (beta-aminothyl ether) N,N,N'N'-tetraacetic acid (EGTA) (0.5 mM), a calcium chelator, to the media blocked A beta-induced IL-1 beta release, but had no effect on LPS-activated THP-1 cell release of IL-1 beta. The presence of 3,4,5-trimethoxybenzoic acid 8-(diethyl amino)-octyl ester (TMB-8), an inhibitor of intracellular calcium mobilization, as well as nickel chloride, a non-specific calcium channel blocker, in the media also inhibited A beta-induced IL-1 release from LPS-activated THP-1 cells. IL- 1 beta release from activated THP-1 monocytes incubated with TMB-8 and nickel chloride without A beta remained at baseline values. Pretreatment of THP-1 monocytes with pertussis toxin for 4 h, followed by LPS activation and incubation with A beta, antagonized the release of IL-1 beta from these cells, but did not alter IL-1 beta release from activated THP-1 monocytes. These data suggest that A beta-induced IL-1 beta release from these cells is calcium-dependent and requires the activation of specific G-proteins. These findings are consistent with known second messengers that are activated following stimulation of chemotactic receptors.
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PMID:beta-Amyloid-induced IL-1 beta release from an activated human monocyte cell line is calcium- and G-protein-dependent. 914 72

Activated macrophages are important cell effectors in sepsis/endotoxemia. Superoxide (SO) and nitric oxide (NO) are produced by activated macrophages and are responsible for host defense against microorganisms. Using laser scanning confocal microscopy, we investigated the role of intracellular free calcium ([Ca2+]i) on SO and NO production by rat peritoneal macrophages activated by lipopolysaccharide (LPS). Calcium influx from the extracellular space versus release of calcium from intracellular stores was determined using calcium channel blockers (diltiazem [DIL], verapamil [VER], and nicardipine [NIC]) and dantrolene (DAN), respectively. Cells incubated with LPS had a 30-50 nM increase in [Ca2+]i, (p < .05) compared with non-LPS-treated cells. When stimulated with phorbol myristate acetate, both control and LPS-treated cells sustained a comparable increase in [Ca2+]i, but [Ca2+]i, remained elevated 30 min later in LPS-treated cells. Calcium channel blockers and DAN reduced phorbol myristate acetate-stimulated SO and LPS-stimulated NO production at all concentrations tested (p < .05). Although increased extracellular calcium influx and calcium from intracellular stores are important regulators of SO and NO production in macrophages, extracellular calcium influx seems to have the predominant effect. Calcium antagonists may modulate the inflammatory response via their effects on macrophages.
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PMID:Calcium antagonists inhibit oxidative burst and nitrite formation in lipopolysaccharide-stimulated rat peritoneal macrophages. 937 63

Pancreatitis complicated with infection often results in the development of multiple organ failure. We investigated the role of altered intracellular calcium as a priming signal for cytokine-induced neutrophil chemoattractant expression in this process. Agents modulating cytosolic Ca2+ were utilized to study the in vivo and in vitro cytokine-induced neutrophil chemoattractant expression for macrophages in rats with cerulein-induced pancreatitis after intraperitoneal administration of lipopolysaccharide as a septic challenge. Pretreatment with the calcium channel blocker verapamil significantly reduced serum cytokine-induced neutrophil chemoattractant concentrations in rats with cerulein-induced pancreatitis after septic challenge. Lipopolysaccharide-stimulated in vitro cytokine-induced neutrophil chemoattractant (CINC) production by peritoneal macrophages was significantly enhanced by pretreatment with thapsigargin (an inhibitor of the endoplasmic reticulum-resident Ca2+-ATPase), but not by A23187 (a calcium-specific ionophore, extracellular Ca2+ influx). Pretreatment with U73122 (a phospholipase C inhibitor) inhibited lipopolysaccharide-stimulated but not basal cytokine-induced neutrophil chemoattractant production, while verapamil (a calcium channel blocker), TMB-8 (an inhibitor of calcium release from endoplasmic reticulum), and W7 (calmodulin antagonist) completely abrogated the chemoattractant production. Altered intracellular calcium, due to Ca2+ efflux from intracellular stores, may be involved in the "priming" of macrophages to release cytokine-induced neutrophil chemoattractant following triggering with lipopolysaccharide during acute cerulein pancreatitis.
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PMID:Intracellular calcium affects neutrophil chemoattractant expression by macrophages in rats with cerulein-induced pancreatitis. 955 45

Recent studies suggested that transmitters released from the sympathetic nerve terminals can modulate various inflammatory responses by occupation of receptors on immune cells. These neurotransmitters act via alteration of intracellular concentration of second messengers. For instance, intracellular calcium as a second messenger plays an important role in the regulation of immune responses. Endotoxemia has been shown to be associated with an increase in cytosolic free calcium concentration ([Ca2+]i). Previously we have demonstrated that the calcium channel blockers verapamil and diltiazem, as well as dantrolene, an agent that blocks the release of calcium from its cytoplasmic stores, inhibits tumor necrosis factor-a (TNF-alpha) and augments interleukin-10 (IL-10) plasma levels in endotoxemic BALB/c mice. Here we investigated the effects of verapamil, diltiazem, and dantrolene on lipopolysaccharide (LPS)-evoked production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) in BALB/c, C57BL/6 IL-10+/+, and the IL-10 deficient C57BL/6 IL-10(0/0) mice. Intraperitoneal (i.p.) pretreatment with dantrolene (20 mg/kg), but not verapamil (10 mg/kg, i.p.) or diltiazem (20 mg/kg, i.p.) suppressed the LPS-induced (80 mg/kg, i.p.) plasma levels of IL-12 and IFN-gamma in BALB/c mice. Similarly to the BALB/c mice, dantrolene increased IL-10 plasma levels in C57BL/6 IL-10+/+ mice. On the other hand, dantrolene suppressed IL-12 and IFN-gamma production in both the C57BL/6 IL-10+/+ and C57BL/6 IL-10(0/0) mice. These data show that calcium entry blockers and dantrolene differentially regulate IL-12 and IFN-gamma production. Furthermore, dantrolene inhibits the IL-12 and IFN-gamma response independently of the increased release of IL-10.
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PMID:Calcium channel blockers and dantrolene differentially regulate the production of interleukin-12 and interferon-gamma in endotoxemic mice. 966 21

Previous studies have demonstrated that intravenous lipopolysaccharide (LPS) will increase concentrations of growth hormone (GH). One possible explanation for this may reside in the response of the pituitary to specific cytokines. This study sought to determine the effects of recombinant bovine tumor necrosis factor alpha (TNF), recombinant ovine (ro) interleukin-1alpha (IL-1alpha), roIL-1beta, ro interleukin-2 (IL-2), and ro gamma-interferon (INT) on GH release from cultured sheep pituitary cells. Sheep were sacrificed and pituitary cells cultured in DMEM with 10% fetal bovine serum for 3 days. On day 4, cells were washed and serum-free DMEM added to cells. IL-1alpha and IL-1beta were used at 0.2, 2 and 20 ng/ml and the remaining cytokines at 2, 20 and 200 ng/ml. Neither IL-2 nor INT had effects on basal or on GH-releasing hormone (GRH)-stimulated GH release. TNF inhibited GRH-stimulated GH release (p < 0.05). Both IL-1alpha and IL-1beta stimulated GH release from cultured pituitary cells at all doses tested (p < 0.01). Neither IL-1alpha nor IL-1beta had an effect on GRH-stimulated GH release. IL-1 effects were inhibited by H-89 (p < 0.05; a protein kinase A inhibitor) and by nifedipine (p < 0.05; a calcium channel blocker). Both of these mechanisms are central signal transduction mechanisms mediating GRH-stimulated GH release. IL-1-stimulated GH release is partially inhibited (p < 0.05) by lipoxygenase pathway blockers. Phorbol myristate acetate downregulation of protein kinase C did not alter IL-1-stimulated GH release. IL-1beta increased the content of both GH and GH mRNA in cultured sheep pituitary cells. We conclude that IL-1 produces a strong stimulus to GH release, which is mediated by calcium entry and protein kinase A activation. IL-1 also activates lipoxygenase pathways. This latter pathway as well as calcium entry were shown to mediate LPS stimulation of GH release from cultured pituitary cells. The similarity between IL-1 and LPS signal transduction suggests that LPS may activate pituitary production of IL-1 to produce the stimulus to GH. The lack of inhibitory effects of INT, TNF and IL-2 as opposed to what is seen in the rat may suggest a partial mechanism to explain the different effects of LPS on GH release between sheep and that seen in cattle and rats.
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PMID:Cytokine-mediated growth hormone release from cultured ovine pituitary cells. 973 4

We recently hypothesized that lipopolysaccharide (LPS) stimulation of rat Kupffer cells to induce tumor necrosis factor alpha (TNF-alpha) release requires internalization of LPS, acidification of endosomes, elevation of intracellular calcium, protein kinase C (PKC) activation, and protein tyrosine kinase (PTK) activation. This study uses inhibitors in pulse-chase experiments to determine the sequence of events of intracellular signals required for LPS-stimulated TNF-alpha release from Kupffer cells. Inhibitors of internalization (cytochalasin B, monodansylcadaverine) prevented LPS-stimulated TNF-alpha release when added simultaneously with LPS but when added 10 min after LPS, no significant inhibition occurred. The inhibitor of PTK, tyrphostin AG, blocked TNF-alpha release by only 39 +/- 4% (P < 0.001 compared with TNF-alpha release when added simultaneously with LPS) when added 10 min after LPS. Inhibitors of endosomal acidification (bafilomycin A, monensin) inhibited LPS-stimulated TNF-alpha release by 92 +/- 11% (P < 0.001 when no inhibitor was used) when added 10 min after LPS and their effect was totally abrogated when added 45 min after LPS. The PKC inhibitor, H-7, blocked TNF-alpha release by 94 +/- 9% (P < 0.001 when no inhibitor was used) when added 30 min after LPS. The calcium channel blocker, nisoldipine, still inhibited LPS-stimulated TNF-alpha release when added 45 min after LPS. These data support the hypothesis that for LPS-stimulated TNF-alpha release in Kupffer cells, LPS must first be internalized, which may stimulate PTK activation. An intermediate step of signaling involves endosomal acidification. Elevation of intracellular calcium and PKC activation occur as late intracellular signaling events.
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PMID:Lipopolysaccharide-stimulated TNF-alpha release from cultured rat Kupffer cells: sequence of intracellular signaling pathways. 973 64

The etiology of Parkinson's disease is not known. Nevertheless a significant body of biochemical data from human brain autopsy studies and those from animal models point to an on going process of oxidative stress in the substantia nigra which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Nevertheless, oxidative stress as induced by neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been used in animal models to investigate the process of neurodegeneration with intend to develop antioxidant neuroprotective drugs. It is apparent that in these animal models radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists do induce neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided also evidence for an inflammatory process. This expresses itself by proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors, NF kappa-beta and elevation of cytotoxic cytokines TNF alpha, IL1-beta, and IL6. Both radical scavengers and iron chelators prevent LPS (lipopolysaccharide) and iron induced activation of NF kappa-B. If an inflammatory response is involved in Parkinson's disease it would be logical to consider antioxidants and the newly developed non-steroid anti-inflammatory drugs such as COX2 (cyclo-oxygenase) inhibitors as a form of treatment. However to date there has been little or no success in the clinical treatment of neurodegenerative diseases per se (Parkinson's disease, ischemia etc.), where neurons die, while in animal models the same drugs produce neuroprotection. This may indicate that either the animal models employed are not reflective of the events in neurodegenerative diseases or that because neuronal death involves a cascade of events, a single neuroprotective drug would not be effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
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PMID:Neuroprotective strategies in Parkinson's disease using the models of 6-hydroxydopamine and MPTP. 1086 45


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