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 studies have demonstrated that exposure of guinea pig macrophages to a primary signal, such as lipopolysaccharide (LPS), stimulates the synthesis of prostaglandin E2 (PGE2) which, in turn, elevates cAMP levels resulting in the production of the enzyme, collagenase. The potential of regulating the biochemical events in this activation sequence was examined with the anti-inflammatory agents dexamethasone and colchicine, which suppress the destructive sequelae in chronic inflammatory lesions associated with the degradation of connective tissue. The addition of dexamethasone with LPS to macrophage cultures resulted in a dose-dependent inhibition of PGE2 and collagenase production, which was reversed by the exogenous addition of phospholipase A2. Collagenase production was also restored in dexamethasone-treated cultures by the addition of products normally produced as a result of phospholipase action, such as arachidonic acid, PGE2 or dibutyryl-cAMP. Since the effect of dexamethasone was thus linked to phospholipase A2 inhibition, mepacrine, a phospholipase inhibitor, was also tested. Mepacrine, like dexamethasone, caused a dose-dependent inhibition of PGE2 and collagenase. In addition to corticosteroid inhibition, colchicine was also found to block collagenase production. However, this anti-inflammatory agent had no effect on PGE2 synthesis. Colchicine was effective only when added at the onset of culture and not 24 h later, implicating a role for microtubules in the transmission of the activation signal rather than enzyme secretion. The failure of lumicolchicine to inhibit collagenase activity provided additional evidence that microtubules are involved in the activation of macrophages. These findings demonstrate that dexamethasone and colchicine act at specific steps in the activation sequence of guinea pig macrophages to regulate collagenase production.
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PMID:Regulation of guinea pig macrophage collagenase production by dexamethasone and colchicine. 632 92

The mechanism of macrophage activation by Ca2+ ionophore was studied. Peritoneal exudate macrophages from normal guinea pigs exposed continuously to or pulse treated for 1 hr with the ionophore, A23187, were activated, manifesting increased glucose consumption and inhibition of migration. Highly purified macrophages were also activated as effectively as crude macrophage preparations, and the culture supernatant of spleen lymphocytes treated with A23187 lacked a macrophage activating effect, showing that the macrophage activation resulted from the direct effect of A23187 on macrophages, not via lymphokines produced by lymphocytes. The macrophage activation by A23187 was suppressed in the presence of EGTA, but the suppressive effect was overcome by the addition of Ca2+, but not of Mg2+. A dilution experiment with Ca2+ and Mg2+ during the pulse treatment of cells with A23187 revealed that the activating effect of A23187 was more dependent on Ca2+ content than Mg2+. In addition, the Ca2+ antagonist, nicardipine, was found to suppress the activating effect of A23187. The Ca2+ uptake into macrophages was increased by treatment with A23187. These results indicate that Ca2+ influx into cells is primarily important in the macrophage activating effect of A23187. Trifluoperazine (TFP: a specific inhibitor of calmodulin that is an intracellular Ca2+ receptor protein) was found to inhibit the activating effect of A23187. Further, the cyclic nucleotides, dibutyryl-cAMP and -cGMP, did not activate macrophages. Therefore, macrophage activation was presumed not to be directly mediated by cyclic nucleotides. All these findings show that macrophage activation with the ionophore proceeds by the following scheme: Ca2+ influx leads to activation of Ca2+ receptor protein, calmodulin leads to activation of calmodulin-regulated enzymes leads to metabolic changes, activation. TFP was found to suppress the macrophage activation with highly purified guinea pig macrophage activation factor/macrophage migration inhibitory factor (MIF/MAF) or lipopolysaccharide (LPS), suggesting that calmodulin also played an important role in macrophage activation with MIF/MAF or LPS.
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PMID:The mechanism of macrophage activation induced by Ca2+ ionophore. 640 51

Guinea pig peritoneal exudate macrophages actively incorporated [3H]thymidine into trichloroacetic acid-insoluble fraction in vitro. The incorporation of [3H]thymidine was almost completely inhibited by aphidicolin, an inhibitor of DNA polymerase alpha and an autoradiograph showed heavy labeling in nuclei of 15% of macrophage populations. These results indicate that the observed thymidine incorporation was due to a nuclear DNA synthesis. The [3H]thymidine incorporation was markedly suppressed when macrophages were activated by immunoadjuvants such as muramyl dipeptide (MDP) or bacterial lipopolysaccharide (LPS). The suppression of [3H]thymidine incorporation by MDP was neither due to the decrease in thymidine transport through the cell membrane, nor due to dilution by newly synthesized "cold" thymidine. An autoradiograph revealed that MDP markedly decreased the number of macrophages the nuclei of which were labeled by [3H]thymidine. These results suggest that the suppression of [3H]thymidine incorporation by the immunoadjuvants reflects a true inhibition of DNA synthesis. The inhibition of DNA synthesis by MDP was also observed in vivo. Further, it was strongly suggested that the inhibition was not caused by some mediators, such as prostaglandin E2, released from macrophages stimulated by the immunoadjuvants but caused by a direct triggering of the adjuvants at least at the early stage of activation. Cyclic AMP appears to be involved in the inhibitory reaction.
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PMID:Inhibition of macrophage DNA synthesis by immunomodulators. II. Characterization of the suppression by muramyl dipeptide or lipopolysaccharide [3H]thymidine incorporation into macrophages. 643 15

The initiation of antigen-specific, T-dependent immune responses by macrophages requires their expression of Ia antigens. Ia antigen-deficient (Ia-) peritoneal exudate or P388D1 cell line macrophages, when incubated for 2 to 3 days with partially purified immune interferon (IFN-gamma), expressed Ia antigen, as detected by antibody-and-complement-mediated cytotoxicity. This paper reports that bacterial endotoxin (lipopolysaccharide, LPS) inhibited both IFN-gamma induction of macrophage Ia antigen expression and IFN maintenance of the Ia+ state in a dose-dependent manner. In the absence of IFN-gamma, LPS had no significant effect on macrophage Ia antigen expression. The inhibitory effects of LPS were abrogated by the addition of indomethacin into the culture medium. Further, 10(-10) to 10(-6) M exogenous prostaglandin E2 or 10(-6) to 10(-4) M exogenous dibutryl 3'5' cyclic adenosine monophosphate also inhibited IFN-gamma regulation of macrophage Ia antigen expression. The data suggest that LPS inhibits IFN-gamma regulation of macrophage Ia antigen expression by stimulating macrophage prostaglandin E2 production, and consequently enhancing intracellular cAMP levels. The data outline an inhibitory pathway involved in the regulation of macrophage Ia antigen expression, and may explain, in part, reported immunosuppressive effects of LPS.
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PMID:Regulation of murine macrophage Ia antigen expression by an immune interferon-like lymphokine: inhibitory effect of endotoxin. 681 67

There is a need for pharmacological agents for the treatment of pulmonary edema associated with the adult respiratory distress syndrome. Therefore, we examined the effects of isozyme-selective cyclic AMP phosphodiesterase (cAMP PDE) inhibitors, as well as aminophylline and dexamethasone, on the pulmonary edema, protein leakage into the airways and airway neutrophilia induced by aerosolized lipopolysaccharide (LPS) in intact guinea pigs. Twenty-four hours after LPS exposure lung wet/dry weight ratios increased from 4.9 +/- 0.004 to 5.8 +/- 0.02. Rolipram (PDE4 selective), CI-930 (PDE3 selective), aminophylline and dexamethasone (given p.o. 1 hr before and 4 hr after LPS exposure) inhibited pulmonary edema formation with ED50 values of 1.7, 0.5, 31 and 2.8 mg/kg, respectively. Maximum inhibition occurred with rolipram at 10 mg/kg (70 +/- 17%), CI-930 at 10 mg/kg (101 +/- 4%), aminophylline at 50 mg/kg (88 +/- 14%) and dexamethasone at 3 mg/kg (64 +/- 6%). Denbufylline and milrinone also inhibited pulmonary edema formation at 10 mg/kg i.p., supporting the inhibition of PDE4 and PDE3 as the mechanisms of action of rolipram and CI-930, respectively. Rolipram, CI-930, aminophylline and dexamethasone (at maximum doses for inhibiting pulmonary edema) inhibited the 3-fold increase in bronchoalveolar lavage albumin concentration 24 hr after LPS exposure (42 +/- 14%, 98 +/- 2%, 70 +/- 9% and 53 +/- 13%, respectively). However, none of these compounds (at maximum doses for inhibiting pulmonary edema) inhibited the corresponding 400-fold increase in lavage neutrophil counts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of lipopolysaccharide-induced pulmonary edema by isozyme-selective phosphodiesterase inhibitors in guinea pigs. 747 57

We assessed the role of cyclic nucleotides in modulating lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) generation in human peripheral blood monocytes. Exposure of monocytes to LPS (3 ng/ml) evoked a delayed, time-dependent generation of TNF-alpha that reached a maximum level 5-6 hr after LPS challenge and remained constant for up to 24 hr. This effect was concentration dependent and resulted in a 20-40-fold increase in the release of TNF-alpha that was sensitive to actinomycin D and cycloheximide. Treatment of monocytes with agents reputed to activate the cAMP/cAMP-dependent protein kinase (PKA) cascade in general inhibited LPS-induced TNF-alpha generation. Thus, the beta 2-adrenoceptor agonists albuterol and procaterol partially (approximately 40%) suppressed TNF-alpha generation in a propranolol-sensitive manner. Furthermore, 8-bromo-cAMP, cholera toxin, prostaglandin E2, and a number of drugs (i.e., rolipram (ZK 62711), denbufylline (BRL 30892), Ro 20-1724, benafentrine (AH 21-132), that inhibit the phosphodiesterase (PDE) 4 isoenzyme family abolished cytokine generation. In contrast, forskolin, inhibitors of PDE3 and PDE5, and activators of soluble and particulate guanylyl cyclase were essentially inactive. Interestingly, rolipram failed to potentiate the inhibitory effect of albuterol on LPS-induced TNF-alpha biosynthesis but, paradoxically, synergized with albuterol in the generation of cAMP and in the activation of PKA. When PGE2 was used to activate adenylyl cyclase, however, rolipram potentiated cAMP accumulation, PKA activation, and inhibition of TNF-alpha generation. In contrast, forskolin did not increase the cAMP content of monocytes in the absence or presence of rolipram. Collectively, these data suggest that LPS-induced TNF-alpha generation by human peripheral blood monocytes is due to increased transcription and subsequent translation of the TNF-alpha gene and that these effects are suppressed by a range of agents that activate the cAMP/PKA cascade. However, the failure of rolipram to potentiate the inhibitory effect of albuterol and procaterol on TNF-alpha generation suggests that beta 2-adrenoceptor agonists may affect gene expression and/or post-transcriptional regulatory processes by, at least in part, a cAMP-independent mechanism(s).
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PMID:Suppression of lipopolysaccharide-induced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl cyclase. 747 3

Exposure of human monocytes (HM) to E. coli lipopolysaccharide (LPS) results in measurable production of both IL-1 beta and TNF alpha in culture supernatants. It has previously been reported that the elevation of cAMP levels in HM selectively suppresses the LPS-induced TNF alpha but not IL-1 beta production. In this study we investigated whether the novel anti-inflammatory drug, SK&F 86002 [5-4(-pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazole(2,1-b)thi azol] and related analogs of the pyridinyl imidazole class, inhibit IL-1 and TNF production via a cAMP-dependent mechanism. These compounds, when added together with LPS result in inhibition of IL-1 and TNF production with equal-rank-order potency. Although the pyridinyl imidazole compounds were found to be generally weak phosphodiesterase inhibitors, they did not affect cAMP levels in HM, alone or in the presence of LPS. In contrast, PGE2, which significantly elevated intracellular cAMP levels, inhibited TNF but not IL-1 production at the transcriptional level. Taken together, these results suggest that the pyridinyl imidazoles inhibit the production of IL-1 beta and TNF alpha through pathways independent of cAMP elevating mechanisms.
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PMID:Inhibition of interleukin-1 (IL-1) and tumor necrosis factor (TNF) production by pyridinyl imidazole compounds is independent of cAMP elevating mechanisms. 750 4

Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) analogs in their potency to influence LPS-stimulated production of interleukin-1 beta (IL-1 beta) and TNF-alpha by human mononuclear cells (MNC). Our results show, that the stable analogs of PGI2, iloprost and cicaprost, markedly suppress TNF-alpha synthesis in LPS-stimulated MNC without effect on IL-1 beta production. Although there was no significant difference in maximal suppression of TNF-alpha, iloprost and cicaprost reached suppression to 50% of control at 20-fold lower concentrations than PGE2. The ID50 for iloprost and cicaprost were 8 nM and 5 nM, respectively, compared to 125 nM for PGE2. Moreover, the prostacyclin analogs as well as PGE2 suppressed LPS-induced production of TNF-alpha in Mono Mac 6 cells, a permanent human cell line with characteristics of mature monocytes. Suppression of TNF-alpha synthesis by cicaprost and PGE2 is probably mediated by an increased intracellular cAMP formation. We were able to show elevated cAMP levels with 1 microM and 10 microM of PGE2 and cicaprost in this system. The suppression of TNF-alpha synthesis may add to the beneficial effects of iloprost reported in animal models of acute respiratory distress syndrome (ARDS) and may offer a therapeutic approach in TNF-alpha mediated pathologic processes.
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PMID:Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells. 750 98

Expression of cytokines can be modulated by cAMP in macrophages or in primary microglial cultures. Similar to what is observed in normal conditions, treatment of immortal microglial cell lines with dibutyryl-cAMP blocked the accumulation of TNF alpha transcripts induced by lipopolysaccharide, whereas activation of Interleukin-1 alpha (IL-1 alpha) remained unaffected. Immortalized cell lines can therefore be regarded as a valid model to test the immune responsiveness of microglial cells in the presence of neuro-endocrine agents modulating cAMP levels.
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PMID:Modulation of cytokine expression by cAMP analogs in myc-immortalized microglial cell lines. 751 57

Among other effects, prostaglandins (PG) of the E series are known to inhibit several acute and chronic inflammatory conditions in vivo and proinflammatory cytokine production by activated macrophages in culture. The research presented here demonstrates that the inhibitory effect of PGE2 on tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production by lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages involves IL-10. In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-alpha and IL-6, but not of lactate or nitric oxide. The decrease in the level of these cytokines is inversely proportional to the increase in immunoreactive IL-10. This differential inhibitory effect of PGE2 is mimicked by agents that elevate intracellular levels of cAMP, but not cGMP. Neutralizing anti IL-10 antibody but not neutralizing antibodies against other macrophage secretory products (IL-6, leukemia inhibitory factor, and transforming growth factor beta [TGF-beta]), significantly reverse the potent inhibitory effect of PGE2. In vivo, the administration of PGE2 before LPS challenge significantly reduces circulating TNF-alpha and IL-6 levels. Anti-IL-10 antibody substantially enhanced the LPS-induced TNF-alpha and IL-6 levels in mice that received either LPS alone or LPS plus PGE2. These results suggest that the anti-inflammatory effect of PGE2 on mononuclear phagocytes is mediated in part by an autocrine feedback mechanism involving IL-10.
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PMID:Evidence for the involvement of interleukin 10 in the differential deactivation of murine peritoneal macrophages by prostaglandin E2. 752 53


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