Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Angiotensin converting enzyme (ACE) is present on endothelial cells and plays a role in regulating blood pressure in vivo by converting angiotensin I to angiotensin II and metabolizing bradykinin. Since ACE activity is decreased in vivo in sepsis, the ability of lipopolysaccharide (LPS) to suppress endothelial cell ACE activity was tested by culturing human umbilical vein endothelial cells (HUVEC) for 0-72 hr with or without LPS and then measuring ACE activity. ACE activity in intact HUVEC monolayers incubated with LPS (10 micrograms/ml) decreased markedly with time and was inhibited by 33%, 71%, and 76% after 24 hr, 48 hr, and 72 hr, respectively, when compared with control, untreated cells. The inhibitory effect of LPS was partially reversible upon removal of the LPS and further incubation in the absence of LPS. The LPS-induced decrease in ACE activity was dependent on the concentrations of LPS (IC50 = 15 ng/ml at 24 hr) and was detectable at LPS concentrations as low as 1 ng/ml. That LPS decreased the Vmax of ACE in the absence of cytotoxicity and without a change in Km suggests that LPS decreased the amount of ACE present on the HUVEC cell membrane. While some LPS serotypes (Escherichia coli 0111:B4 and 055:B5, S. minnesota) were more potent inhibitors of ACE activity than others (E. coli 026:B6 and S. marcescens), all LPS serotypes tested were inhibitory. These finding suggest that LPS decreases endothelial ACE activity in septic patients; in turn, this decrease in ACE activity may decrease angiotensin II production and bradykinin catabolism and thus play a role in the pathogenesis of septic shock.
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PMID:Lipopolysaccharides decrease angiotensin converting enzyme activity expressed by cultured human endothelial cells. 131 Mar 27

Angiotensin converting enzyme (ACE;EC 3.4.15.1), or kininase II, was studied in serum, cultured endothelial cells from cord artery, in macrophages of humans, and in serum and purified plasma membranes of rats following treatment with inducers of ACE biosynthesis. ACE activity was measured in biological fluids with an enzyme kinetic method employing synthetic 1-hipp-1-his-l-leu tripeptide as a substrate, and with a new method using 125I-labelled specific inhibitor of ACE as a sensitive probe for ACE binding sites. The latter technique also proved suitable for the quantification of ACE in cells. Anti-human ACE antibody was employed for immunofluorescence studies in human cells. Dexamethasone treatment caused an increase in ACE in cultured human endothelial cells, macrophages and in rat pulmonary plasma membranes, but failed to increase serum ACE activity in rats. Captopril and enalapril treatment of hypertensive patients increased total serum ACE, the increase being evident after removal of the active drug from the serum by prolonged storage or chloramine T treatment (captopril) or by dialysis (enalapril). Captopril increased the ACE content of endothelial cells and macrophages. Macrophages appeared sensitive to captopril induction of ACE biosynthesis after pre-stimulation with Escherichia coli lipopolysaccharide. Dexamethasone treatment potentiated the known induction of ACE in rat pulmonary tissue. Thus ACE biosynthesis may be enhanced by three categories of treatment: (1) glucocorticoid; (2) macrophage activation; (3) ACE inhibitors. The precise mechanism of ACE induction and its possible biological relevance await further clarification.
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PMID:Regulation of angiotensin converting enzyme. 610 Jun 6

Previous studies from our laboratories demonstrated that human decidual macrophages and peripheral mononuclear cells express renin. In the present study, we found that U-937 monocytes, induced to differentiate into macrophage-like cells by treatment with phorbol dibutyrate (PDBU), express renin mRNA and release renin (95%, of which is in the form of prorenin). Treatment of these PDBU-exposed cells with dibutyryl-cAMP (1 mM) caused a 20-fold increase in renin mRNA and a 10-fold increase in prorenin release. Forskolin (10 microM), an activator of adenylyl cyclase, and terbutaline (100 microM), a beta2-adrenergic agonist known to increase cAMP levels, also increased renin mRNA and prorenin release. The secretory response to terbutaline was potentiated by the type IV cyclic AMP-phosphodiesterase (PDE) inhibitor Ro 20-1724 (50 microM). Angiotensin II agonist inhibited the stimulatory effect of terbutaline on renin secretion as did the cytokines tumor necrosis factor-alpha and lipopolysaccharide plus interferon-gamma. Since other studies have shown that U-937 cells possess beta2-adrenergic receptors and express mainly the type IV PDE, the present findings strongly suggest that beta-adrenergic receptors in mononuclear cells are coupled to renin expression via the cAMP transduction pathway. The results support a possible role for the renin-angiotensin system in macrophage function and suggest potential autocrine regulatory mechanisms in prorenin expression.
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PMID:Beta-adrenergic regulation of renin expression in differentiated U-937 monocytic cells. 925 63

Angiotensin converting enzyme (ACE) inhibitors have immunomodulatory functions and can suppress a number of proinflammatory, monocyte/macrophage-derived cytokines. Interleukin-12 is a cytokine produced primarily by monocytes and macrophages, which plays an essential role in cell mediated immunity and stimulates the development of T helper type 1 immune responses. In this study, we investigated the ability of ACE inhibitors, captopril and lisinopril, to suppress IL-12 production by human peripheral blood mononuclear cells (PBMC). We show that both ACE inhibitors significantly inhibit production of IL-12 by PBMC stimulated with bacterial lipopolysaccharide (LPS) or Staphylococcus aureus Cowan (SAC). Although both ACE inhibitors also suppressed IFN-gamma production by human anti-CD3/anti-CD28-stimulated T-cells, the addition of exogenous IFN-gamma to the PBMC stimulation medium does not abrogate the ability of ACE inhibitors to suppress IL-12 production. Inhibition of IL-12 was not associated with inhibition of IL-1beta, but correlated with the suppression of ACE. Therefore, suppression of IL-12 may contribute to the immunomodulatory effect of ACE inhibitors and may be responsible for the beneficial effect of captopril and other ACE inhibitors in inflammatory or autoimmune conditions in which IL-12 is involved.
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PMID:Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells. 967 44

This study aimed to examine whether lipopolysaccharide (LPS)-induced increase in tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) gene transcription was regulated by beta-adrenoceptor activation and whether TNF-alpha and IL-6 gene transcription was regulated by angiotensin II in rat renal resident macrophage cells. The cells were transfected with a fusion gene with the 5'-flanking region of rat TNF-alpha or IL-6 genes linked to a luciferase coding sequence as a reporter. The stimulatory effect of LPS on TNF-alpha transcription was suppressed by isoproterenol (10(-8)-10(-5)M) in a dose-dependent manner, whereas IL-6 transcription was only decreased by the high concentration (10(-5)M) of isoproterenol. The addition of beta(2)-adrenoceptor antagonist (ICI118,551), but not a beta(1)-adrenoceptor antagonist (atenolol), blocked the inhibitory effect of isoproterenol. By contrast, angiotensin II (10(-8)-10(-5)M) enhanced IL-6 gene transcription in the cells in a dose-dependent manner which was inhibited by type 1 angiotensin II receptor antagonist (CV11,974). TNF-alpha and IL-6 secretion from the cells was altered with beta(2)-adrenoceptor agonists (terbutaline, formoterol) and angiotensin II corresponding to changes of TNF-alpha and IL-6 gene transcription. Angiotensin II had no effect on TNF-alpha secretion and gene transcription. These findings suggested that beta(2)-adrenoceptor agonist and angiotensin II potentially could influence renal immune function through the regulation of TNF-alpha and IL-6 gene transcription by the renal resident macrophage cells.
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PMID:Effect of beta(2)-adrenoceptor activation and angiotensin II on tumour necrosis factor and interleukin 6 gene transcription in the rat renal resident macrophage cells. 1052 14

Angiotensin II (ANG II) and nitric oxide (NO) have contrasting vascular effects, yet both sustain inflammatory responses. We investigated the impact of ANG II on lipopolysaccharide (LPS)/interferon-gamma (IFN)-induced NO production in cultured rat mesangial cells (MCs). LPS/IFN-induced nitrite production, the inducible form of nitric oxide synthase (NOS-2) mRNA, and protein expression were dose dependently inhibited by ANG II on coincubation, which was abolished on ANG II type 2 (AT(2)) receptor blockade by PD-123319. Homology-based RT-PCR verified the presence of AT(1A), AT(1B), and AT(2) receptors. To shift the AT receptor expression toward the type 1 receptor, two sets of experiments were performed: LPS/IFN preincubation for 24 h was followed by 8-h coincubation with ANG II; or during 24-h coincubation of LPS/IFN and ANG II, dexamethasone was added for the last 6-h period. Both led to an amplified overall expression of NOS-2 protein and NO production that was inhibitable by actinomycin D in the first setup. Induced NO production was enhanced via the AT(1) receptor; however, it was diminished via the AT(2) receptor. In conclusion, induced NO production is negatively controlled by the AT(2), whereas AT(1) receptor stimulation enhanced NO synthesis in MCs. The overall NO availability depended on the onset of the inflammatory stimuli with respect to ANG II exposure and the available AT receptors.
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PMID:Angiotensin II receptor subtypes determine induced NO production in rat glomerular mesangial cells. 1109 28

Nitrated tyrosine, implicated in protein dysfunction, is increased in various tissues in association with diverse pathological processes. Angiotensin converting enzyme (ACE) is a luminal vascular endothelial enzyme whose dysfunction is an early sign of endothelial injury. ACE contains a tyrosine critical for its enzymatic activity. Others have shown that nitrite exacerbates the ACE dysfunction of cultured endothelial cells in contact with activated polymorphonuclear neutrophils (PMN). We hypothesized that exogenous nitrite would enhance endothelial ACE dysfunction associated with PMN activation in the isolated lung. Rats received lipopolysaccharide (LPS) 2 h prior to isolated lung perfusion with Ficoll containing buffer. Either formyl-Met-Leu-Phe (fMLP, 10(-7) M) or phorbol myristate acetate (PMA, 10(-7) M) was used to activate PMN in lungs treated or not treated with 300-microM nitrite. A first pass indicator dilution method and first order reaction kinetics were used to determine ACE activity, while lung Ficoll content served as an index of vascular permeability. Both fMLP and PMA decreased endothelial ACE activity and increased pulmonary artery pressure, edema and vascular permeability. Exogenous nitrate did not potentiate the decrease in ACE activity, the lung injury or nitrotyrosine immunoreactivity of lung homogenates. In contrast to observations in cultured endothelial cells, our findings in the whole lung are compatible with the speculation of others that the rat lung has an unidentified factor, which minimizes accumulation of nitrated proteins.
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PMID:Effect of nitrite on endothelial function in isolated lung. 1148 89

Angiotensin II (ANG II), a bioactive peptide that plays important roles in blood-pressure and body-fluid regulation, has recently been reported to be involved in normal thermoregulation and fever. In the case of thermoregulation, ANG II lowers body temperature when administered centrally or systemically (i.e. "exogenous" ANG II acts as a hypothermia-inducing agent). In contrast, "endogenous" ANG II is involved both in heat-loss responses in a hot environment and in thermogenesis in the cold. It therefore seems likely that endogenous ANG II is involved in maintaining body temperature at the set-point. In the case of fever, it has been reported that endogenous brain ANG II and its type 1 receptor mediate or modulate the fever induced by "restraint stress". At the final step in "pyrogen-induced" fever, brain ANG II facilitates the fever induced by prostaglandin E2 (PGE2) through its action on the type 2 receptor, whereas at its first step the lipopolysaccharide (LPS, 2 microg/kg, i.v.)-induced production of pyrogenic cytokines [such as interleukin-1 (IL-1)] involves an action of endogenous ANG II through its type 1 receptor. On the other hand, it is well known that a very high dose of LPS (50-5000 microg/kg) injected systemically induces hypothermia in rodents. This hypothermia is presumably initiated by tumor necrosis factor (TNF). Since ANG II contributes to the LPS-induced production of cytokines such as IL-1beta, as described above, it is possible that the generation of TNF by LPS involves an action of ANG II, too, and that this TNF production leads to the LPS-induced hypothermia. Together, these findings suggest that ANG II and its receptors make a number of contributions to normal thermoregulation, to fever, and to the hypothermia in systemic inflammation.
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PMID:Angiotensin II: its effects on fever and hypothermia in systemic inflammation. 1476 80

Angiotensin II (Ang II) type 1 receptor (AT1R) has been confirmed to confer renoprotection in the progressive, immune-mediated nephritis in animal models as well as in humans. However, the relative contributions of direct AT1R blockade, indirect counteractivation of Ang II type 2 receptor (AT2R), or both, to renoprotection through AT1R antagonism remains to be clarified. Immunohistochemical studies in the nephritic kidney revealed that tubular epithelial cells and infiltrating immune cells were positive for AT1R and AT2R. In the present study, we investigated the action of Ang II on both receptors on immune cells. A subpopulation of lipopolysaccharide-activated splenic lymphocytes (mixed lymphocyte populations) was positive for AT1R and AT2R. Ang II alone could not induce gene expression of a pro-inflammatory chemokine JE or a pro-fibrotic cytokine transforming growth factor-beta1 in those cells. However, Ang II could significantly suppress the expression of both genes in those cells under AT1R blockade, and this action was mediated through AT2R. Conversely, the pro-inflammatory/pro-fibrotic gene expression could be enhanced by AT2R blockade, and this was mediated through AT1R. AT1R and AT2R expressed in activated immune cells can modulate pro-inflammatory and pro-fibrotic reactions reciprocally. In advanced immune-mediated nephritic kidneys, AT1R antagonism likely confers renoprotection via activation of AT2R.
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PMID:Angiotensin II type 1 and type 2 receptors reciprocally modulate pro-inflammatory/ pro-fibrotic reactions in activated splenic lymphocytes. 1514 59

The adrenal gland secretes several cytokines, and cytokines modulate steroid secretion by this gland. In this study, a survey of cytokine production by H295R human adrenocortical cells demonstrated that these cells secreted IL-2, IL-4, IL-8, IL-10, IL-13, and TNFalpha but not IL-5, IL-12, or interferon-gamma. IL-8 was the IL secreted at higher concentration. IL-8 secretion, its regulation, and role in steroidogenesis were further studied. Secreted ILs and steroids were measured by ELISA in cell culture supernatant. IL-8 mRNA was quantified by real-time RT-PCR. H295R cells and human adrenal gland expressed IL-8 mRNA. Angiotensin II, potassium, endothelin-1, IL-1alpha, IL-1beta, TNFalpha, and Escherichia coli lipopolysaccharide dose-dependently increase IL-8 secretion by H295R cells after 24 h incubation. IL-6 had no effect on IL-8 secretion. Angiotensin II time-dependently increased IL-8 secretion by H295R cells up to 48 h. Angiotensin II caused a biphasic increase in IL-8 mRNA expression with a peak 6 h after stimulation. TNFalpha synergized angiotensin II, potassium, and IL-1alpha-mediated IL-8 secretion. IL-8 did not modify aldosterone or cortisol secretion by H295R cells under basal or stimulated (angiotensin II or potassium) conditions. In conclusion, it is demonstrated for the first time that human adrenal cells expressed and secreted IL-8 under the regulation of angiotensin II, potassium, endothelin-1, and immune peptides. Adrenal-secreted IL-8 is one point of convergence between the adrenal gland and the immune system and may have relevance in physiological and pathophysiological conditions associated with increased levels of aldosterone secretagogues and the immune system.
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PMID:Interleukin-8 synthesis, regulation, and steroidogenic role in H295R human adrenocortical cells. 1626 56


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