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)

Trehalose dimycolate (TDM), a mycobacterial glycolipid, is a powerful macrophage-priming agent. However, its efficiency seems limited in the case of BALB/c mice. Peritoneal macrophages harvested from TDM-treated BALB/c mice did not control BCG growth in vitro as efficiently as similar macrophages from two other mouse strains, (B6 x D2)F1 and C57BL/6, which are respectively Bcgr and Bcgs. BALB/c macrophages elicited by TDM also exhibited a low capacity to produce hydrogen peroxide and, after activation by lipopolysaccharide (LPS), weak cytostatic activity against P815 mastocytoma cells. Finally, alkaline phosphodiesterase, a marker of resident and inflammatory macrophages, was still expressed at a high level in macrophages of BALB/c mice treated with TDM. Low responsiveness of BALB/c macrophages to stimuli was not observed with TDM only; activation for tumor cytotoxicity of thioglycolate-elicited macrophages from BALB/c mice required also higher doses of interferon-gamma, and LPS. L-Arginine-dependent production of nitric oxide was inducible in macrophages from BALB/c mice, but the conditions required for its induction were more stringent. Thus, the reduced antiproliferative effects of BALB/c macrophages may be due to uncomplete induction of NO synthase after suboptimal stimulation.
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PMID:Low response of BALB/c macrophages to priming and activating signals. 138 43

Interleukin-1 receptor antagonist (IRA) is a secretory product of human monocytes or related cell lines that acts as a pure interleukin-1 (IL-1) antagonist in several bioassays. IRA administration was reportedly a life-saving intervention in rabbits injected with lethal doses of bacterial lipopolysaccharide (LPS). We report the inhibitory effect of IRA on three distinct types of vascular responses to IL-1 in rabbit isolated blood vessels. The rabbit isolated superior mesenteric artery, when precontracted with phenylephrine, relaxed in a sustained manner in less than 30 min following application of recombinant interleukin-1 beta (12-290 pM), and this was a prostaglandin (PG)-dependent and endothelium-independent process. IRA (human recombinant sequence; 0.9-15 nM) behaved as an antagonist of IL-1 alpha or IL-1 beta, based on the surmountability and the concentration dependence, but could only prevent the effect of IL-1, not reverse it. IRA had no direct effect on the preparation and did not influence the acute relaxing effect elicited by substance P or iloprost, a PGI2 mimetic. Exposure to IL-1 beta depressed the response to noradrenaline (NA) in several hours in rabbit aorta rings. The inhibitory effect of IL-1 beta was endothelium and prostaglandin independent, but was prevented by a treatment with NG-nitro-L-arginine (a nitric oxide synthesis inhibitor), cycloheximide, dexamethasone, or IRA. Using the residual NA-induced contraction as a quantification of the IL-1 agonist effect, IRA was a very potent antagonist of IL-1 beta but was not totally surmountable.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of interleukin-1 receptor antagonist on three types of responses to interleukin-1 in rabbit isolated blood vessels. 138 81

Immunostimulated peritoneal macrophages of mice and rat have been demonstrated to produce L-arginine-derived nitrogen oxides. This metabolic pathway has also recently been found in rat alveolar macrophages and is suggested to play a certain role in lung injury. In vitro nitrite production from alveolar macrophages stimulated in vitro with lipopolysaccharide and recombinant interferon-gamma was inhibited by the addition of the irreversible serine-protease inhibitors, N-tosyl-L-phenylalanine chloromethyl-ketone (3 x 10(-7)-3 x 10(-4) M) and N-tosyl-L-lysine chloromethyl-ketone (3 x 10(-7)-3 x 10(-4) M) in a concentration-dependent manner. Two reversible inhibitors, N-alpha-p-tosyl-L-arginine methyl ester hydrochloride and benzoyltyrosine ethyl ester, were also effective but to a lesser extent. These antiproteases provide an opportunity to study the modulating influence on this recently discovered inflammatory pathway in alveolar phagocytic cells.
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PMID:Serine-protease inhibitors modulate nitric oxide-synthase activity of alveolar macrophages. 138 78

In the skin, wounding initiates a complex array of physiological processes mediated by growth factors and inflammatory mediators which stimulate tissue repair and protect against infection. We report that primary cultures of human keratinocytes and a mouse keratinocyte cell line respond to the inflammatory stimuli gamma-interferon and lipopolysaccharide or tumor necrosis factor-alpha by producing nitric oxide and hydrogen peroxide, two reactive mediators that are important in nonspecific host defense. Nitric oxide is produced by the l-arginine- and NADPH-dependent enzyme, nitric oxide synthase. In murine keratinocytes, optimal enzymatic activity was found to be dependent on Ca2+ and calmodulin as well as on glutathione. Inflammatory mediators were also found to inhibit the growth of keratinocytes, an effect that could be reversed by a nitric oxide synthase inhibitor. Epidermal growth factor (EGF), which promotes wound healing by stimulating cellular proliferation, was found to be a potent antagonist of reactive nitrogen and reactive oxygen intermediate production by keratinocytes. EGF also reversed the growth inhibitory actions of the inflammatory mediators. These data suggest that nitric oxide produced by keratinocytes is important in the control of cellular proliferation during wound healing. Our findings that EGF effectively regulates the production of free radicals by keratinocytes may represent an important pathway by which this growth factor not only stimulates epidermal cell proliferation but also facilitates the resolution of inflammation following wounding.
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PMID:Epidermal growth factor suppresses nitric oxide and hydrogen peroxide production by keratinocytes. Potential role for nitric oxide in the regulation of wound healing. 138 21

In the current study, we describe cytokine and Escherichia coli lipopolysaccharide (LPS) induction of nitric oxide (NO) synthase mRNA levels in cultured smooth muscle from rat pulmonary artery (RPASM). Exposure of RPASM to interleukin-1 beta, interferon-gamma, or LPS alone did not significantly affect NO synthesis, as determined by nitrite concentrations in media. Exposure to tumor necrosis factor-alpha caused a modest (2x) increase in nitrite production. In contrast, exposure to a combination of the above three cytokines and LPS caused a large increase in NO synthesis. Exposure of RPASM to this combination caused an increase in mRNA levels of NO synthase (as described by Northern blot analysis with 32P-cDNA probe to an inducible form of NO synthase present in murine macrophages) that was apparent as early as 4 h. Expression of the induced gene product after exposure to the cytokine and LPS mixture was evident by significant increases in nitrite production at 12 h. Production of nitrite was completely abolished in the presence of NG-monomethyl-L-arginine (NMA), and this inhibition was reversible by the addition of excess L-arginine. NO synthase mRNA levels were not affected by NMA. The nitrite production induced by the combination of cytokines and LPS was abolished by pretreating cells with cycloheximide. These data indicate that a combination of cytokines and LPS affect expression of the gene for the inducible form of NO synthase in cultured RPASM.
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PMID:Cytokines and lipopolysaccharide induce nitric oxide synthase in cultured rat pulmonary artery smooth muscle. 138 80

The role of the endothelium in the hyporesponsiveness of alpha-adrenoceptor-mediated contractions of the rat aorta was investigated. The norepinephrine-induced maximal contraction was diminished after repeated addition of the agonist. The hyporesponsiveness of the maximal contraction was endothelium dependent, being prevented by NG-monomethyl-L-arginine (0.5 mM), L-argininosuccinic acid (0.5 mM), puromycin (IC50 = 100 microM), actinomycin D (IC50 = 80 nM) but not by indomethacin, which suggests that nitric oxide (NO) synthase is induced. The sensitivity of the rings to NO-induced relaxation remained unchanged. The above-mentioned hyporesponsiveness of norepinephrine-induced maximal contractions of aorta rings was also observed after a 5-h incubation without norepinephrine. The agonist-independent hyporesponsiveness was also prevented by NG-monomethyl-L-arginine, puromycin and actinomycin D, which suggests that NO synthase is induced. Moreover, the norepinephrine-independent hyporesponsiveness was prevented by polymyxin B (10 micrograms/ml), which suggests that bacterial lipopolysaccharide (LPS) might be involved. The concentration of contaminating LPS was 89 +/- 11 ng/ml. When the concentration of contaminating LPS was reduced to 40-70 pg/ml, the hyporesponsiveness of the maximal contraction did not occur after repeated addition of norepinephrine or alter a 5-h incubation without the agonist. An addition of 30 or 100 ng/ml of E. coli lipopolysaccharide to the organ bath reproduced the hyporesponsiveness of the maximal contraction. After a 5-h incubation of aortic rings with 30 ng/ml LPS, only the endothelium-intact ring showed a reduced contraction. However, a 24-h incubation reduced the contraction even in the absence of endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelium-accelerated hyporesponsiveness of norepinephrine-elicited contraction of rat aorta in the presence of bacterial lipopolysaccharide. 138 73

The present study was carried out to determine the effector mechanism of anti-Trypanosoma cruzi activity by interferon (IFN)-gamma plus lipopolysaccharide (LPS)-treated macrophages. A macrophage cell line (IC-21) that failed to mount an appreciable oxidative burst was nevertheless found able to control T. cruzi growth after exposure to IFN-gamma alone or IFN-gamma plus LPS. Moreover, microbicidal functions of both inflammatory macrophages and IC-21 against T. cruzi was found to be inhibited in the presence of NG-monomethyl-L-arginine (NGMMA), a competitive inhibitor of L-arginine. Addition of supplemental L-arginine to the culture overcame the capacity of NGMMA to block activated macrophage anti-T. cruzi functions. The ability of NGMMA to reverse both parasite growth inhibition and killing by IFN-gamma plus LPS-activated macrophages was found to correlate with the suppression of nitrite accumulation in the culture supernatants. Together, these results implicate the L-arginine-dependent production of nitric oxide in T. cruzi killing by activated macrophages. We also tested the ability of interleukin(IL)-10 and transforming growth factor (TGF)-beta, to block regulation of T. cruzi growth in this system. Both IL-10 and TGF-beta inhibited anti-parasite function by IFN-gamma-activated macrophages, with an optimal dose of 100 units/ml and 0.5 ng/ml, respectively. Moreover, when used in combination, suboptimal doses of IL-10 and TGF-beta were found to produce a synergistic inhibitory effect in the regulation of T. cruzi growth. The ability of IL-10 and TGF-beta to suppress microbicidal function was also positively correlated with inhibition of nitrite generation in macrophage culture supernatants. These results predict an in vivo role for IL-10 and TGF-beta in promoting parasite survival in the face of the host cell-mediated immune response.
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PMID:The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. 139 57

We have studied the effects of highly purified rabbit lipopolysaccharide (LPS)-binding protein (LBP) on the ability of murine bone marrow-derived macrophages to respond to bacterial LPS. Macrophage responses studied include the secretion of tumor necrosis factor alpha, production of arginine-derived nitrite (NO2-), and killing of an intracellular pathogen, Leishmania enriettii. Macrophages from either CBA or LPS-hyporesponsive C3H/HeJ mice exhibited significantly greater sensitivity to LPS in the presence of LBP. Furthermore, both CBA and C3H/HeJ macrophages demonstrated an LBP-dependent enhancement of LPS binding. These results suggest that C3H/HeJ macrophages are capable of binding LPS-LBP complexes and support the hypothesis that hyporesponsiveness in this strain involves a step subsequent to LPS binding. Furthermore, these findings provide additional evidence of the important role played by the acute-phase plasma protein LBP in modifying host response to LPS.
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PMID:Enhancement of murine macrophage binding of and response to bacterial lipopolysaccharide (LPS) by LPS-binding protein. 140 86

Within the acidic inflammatory milieu, macrophages (m phi s) must maintain their cytoplasmic pH (pHi) within a range conducive to optimal function. It was previously shown that metabolism of L-arginine at concentrations present in vitro in RPMI medium (1.14 mM) impairs the ability of m phi s to regulate pHi. However, concentrations of L-arginine in vivo reportedly range from approximately 100 microM in serum to less than or equal to 50 microM in wounds. To investigate the potential in vivo relevance of this inhibition, m phi pHi regulation was examined following incubation with low concentrations of L-arginine that mimic the inflammatory microenvironment, in the presence or absence of lipopolysaccharide (LPS). pHi regulation was evaluated as the ability of thioglycolate-elicited murine peritoneal m phi s to recover from an imposed cytoplasmic acid load. The m phi pHi was measured using a pH-sensitive fluorescent probe. Following incubation for 2 h in the absence of LPS, the pHi recovery rate was equivalent in cells incubated with and without L-arginine. Coincubation with LPS, however, resulted in marked inhibition of pHi recovery at L-arginine concentrations as low as 12.5 microM. The inhibition was not due to LPS alone, since LPS without L-arginine was not inhibitory. Inhibition of pHi recovery was observed at LPS concentrations ranging from 10 ng/ml to 10 micrograms/ml. The L-arginine-dependent inhibition was apparent within 60 min of exposure to LPS, in both freshly harvested cells and cells preincubated for 2 h in the absence of L-arginine and then exposed to both L-arginine and LPS. Under conditions mimicking the in vivo setting, LPS-stimulated L-arginine metabolism impairs m phi pHi regulation. Modulation of pHi by this mechanism may compromise m phi function within the acidic microenvironment of inflammation.
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PMID:Lipopolysaccharide impairs macrophage cytoplasmic pH regulation under conditions simulating the inflammatory microenvironment. 140 89

1. A closed system was developed for perfusing J774 macrophages in columns. The cells were perfused for up to 100 h, at which time they were still viable. 2. Stimulation with increasing concentrations (0.01-10 micrograms ml-1) of bacterial lipopolysaccharide (LPS) caused the cells to produce increasing amounts of nitrite in the perfusion medium. This production was time-dependent, reaching a plateau by 48-50 h. 3. The nitrite accumulation caused by 0.1 microgram ml-1 of LPS was augmented by priming the cells for 2 h with increasing amounts of interferon-gamma. The nitrite accumulation also reached a plateau under these conditions. 4. N-iminoethyl-L-ornithine (L-NIO, 30 microM) completely inhibited the accumulation of nitrite whereas dexamethasone (0.3 microM) caused 60-70% inhibition. 5. Perfusion of the cells without L-arginine prevented the nitrite accumulation. Replacement of this amino acid after 20 or 50 h of perfusion led to a rapid generation of nitrite, the levels of which continued to increase for the duration of the experiment. 6. Thus, the perfusion system can be used to study the kinetics of the activation of the NO synthase and most likely other parameters in J774 cells and probably other cells in culture. An observation already of interest is that the 'disappearance' of the NO synthase after its activation can be prevented or reduced by removal of L-arginine from the medium.
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PMID:A perfusion system for the long term study of macrophage activation. 142 83


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