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)

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent inhibitory agent in all major forms of inflammation. To identify a potential mechanism of antiinflammatory action of alpha-MSH, we tested its effects on production of nitric oxide (NO), believed to be a mediator common to all forms of inflammation. We measured NO and alpha-MSH production in RAW 264.7 cultured murine macrophages stimulated with bacterial lipopolysaccharide and interferon gamma. alpha-MSH inhibited production of NO, as estimated from nitrite production and nitration of endogenous macrophage proteins. This occurred through inhibition of production of NO synthase II protein; steady-state NO synthase II mRNA abundance was also reduced. alpha-MSH increased cAMP accumulation in RAW cells, characteristic of alpha-MSH receptors in other cell types. RAW cells also expressed mRNA for the primary alpha-MSH receptor (melanocortin 1). mRNA for proopiomelanocortin, the precursor molecular of alpha-MSH, was expressed in RAW cells, and tumor necrosis factor alpha increased production and release of alpha-MSH. These results suggest that the proinflammatory cytokine tumor necrosis factor alpha can induce macrophages to increase production of alpha-MSH, which then becomes available to act upon melanocortin receptors on the same cells. Such stimulation of melanocortin receptors could modulate inflammation by inhibiting the production of NO. The results suggest that alpha-MSH is an autocrine factor in macrophages which modulates inflammation by counteracting the effects of proinflammatory cytokines.
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PMID:Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. 754 12

The aim of the present study was to determine whether two classical macrophage activators, bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) could affect the accumulation of the second messenger cAMP in cultured rat microglia and astrocytes. Purified microglia and astrocyte secondary cultures obtained from the neonatal rat were grown for 3 days in basal medium Eagle (BME) + 10% fetal calf serum (FCS). Exposure of microglia to LPS resulted into a dose- and time-dependent decrease in the accumulation of cAMP induced by receptor-mediated (isoproterenol or prostaglandin E2) or direct (forskolin) activation of adenylate cyclase. The inhibitory effect of LPS was rapid (a 10 min preincubation was sufficient to approach a maximal effect), occurred at low doses (IC50 = 1.2 ng/ml), and was not abrogated by pertussis toxin. A selective inhibitor of type IV phosphodiesterase (rolipram, 100 nM) prevented the effect of LPS on cAMP accumulation, while inhibitors of other forms of phosphodiesterase were unable to do so. IFN-gamma (100 u/ml) also caused a depression of the evoked cAMP accumulation in microglia after a 10 min preincubation, and its effect was prevented by rolipram, as in the case of LPS. Astrocytes differed from microglia in that LPS (1-100 ng/ml) did not inhibit the accumulation of cAMP induced by either isoproterenol or forskolin; on the other hand, IFN-gamma did have an inhibitory effect (though less pronounced than in microglia) that could be prevented by rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interferon-gamma and lipopolysaccharide reduce cAMP responses in cultured glial cells: reversal by a type IV phosphodiesterase inhibitor. 755 45

Interleukin-1 (IL-1) receptors with kinetics, pharmacological and biochemical characteristics of type I IL-1 receptors have been identified in the mouse neuro-endocrine-immune axis. In the present study, we examined the in-vitro and in-vivo modulation of IL-1 receptors by stress and endotoxin treatment. The treatment of AtT-20 mouse pituitary adenoma cells for 24 hr with neuro-endocrine mediators of stress such as corticotropin releasing factor (CRF) and catecholamine (beta 2 adrenergic) receptor agonists produced a dose-dependent increase in cAMP and [125I]IL-1 alpha binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF-stimulated cAMP production and decreased both basal and CRF-mediated increase of [125I]IL-1 alpha binding. Furthermore, in keeping with the effects of stress mediators to upregulate IL-1 receptors in AtT-20 cells, ether-laparotomy stress in mice resulted in a significant increase in [125I]IL-1 alpha binding in the pituitary with no significant alterations observed in the brain; in contrast, [125I]oCRF binding in the pituitary was significantly decreased after the ether-laparotomy stress. Next, we investigated the modulation of IL-1 beta levels and [125I]IL-1 alpha binding following endotoxin lipopolysaccharide (LPS) treatment. IL-1 beta levels were dramatically increased in the peripheral tissues (pituitary, testis and spleen) at 2-6 hr after a single LPS injection (30 micrograms LPS/mouse). However, no significant changes were observed in brain (hippocampus and hypothalamus). [125I]IL-1 alpha binding in the pituitary gland, liver, spleen and testis was significantly decreased at 2 hr following a single administration of both low (30 micrograms LPS/mouse) and high (300 micrograms LPS/mouse) doses of endotoxin. [125I]IL-1 alpha binding in the hippocampus was not significantly altered at 2 hr by a low dose of LPS and was significantly decreased by high dose administration of LPS (300 micrograms/mouse). Following two LPS injections (at 0 and 12 hr), dramatic increases in IL-1 beta concentrations in the hypothalamus, hippocampus, spleen and testis were observed at 2 hr after the second LPS injection; a small but statistically nonsignificant change was evident in the pituitary. Moreover, dramatic decreases in [125I]IL-1 alpha binding were seen after two injections of 30 micrograms LPS/mouse in both central and peripheral tissues. These data provide further support for a role for IL-1 in co-ordinating neuro-endocrine-immune responses to stress and infection.
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PMID:Modulation of interleukin-1 receptors in the neuro-endocrine-immune axis. 757 73

The interleukin-1 (IL-1) system is constituted by IL-1 alpha and IL-1 beta and IL-1 receptor antagonist (IL-1ra) that bind the same IL-1 receptors. Hypothalamic-pituitary-adrenal axis hormones are major mediators of the neuroendocrine control over immune function. Corticotropin-releasing hormone (CRH) is produced in peripheral inflammatory sites; its direct effects on inflammatory cytokine synthesis, however, remain unclear. We have studied the effects of CRH (0.1-100 nM) on IL-1 beta and IL-1ra expression by human peripheral monocytes in culture activated with different doses of lipopolysaccharide (LPS). In the absence of LPS, CRH up-regulated IL-1ra and IL-1 beta messenger RNA expression as well as protein synthesis. No significant changes were observed with low doses of LPS (1 ng/ml). In contrast, in combination with high doses of LPS (1 microgram/ml), CRH caused inhibition of IL-1ra and IL-1 beta transcription and secretion. The CRH effects were blocked by its antagonist alpha-helical CRH and mediated by intracellular cAMP. These data indicate that CRH modulates the IL-1 system; depending on the state of activation of the monocyte, CRH exerts an inhibitory control on the activated cell and a stimulatory action on the resting monocyte.
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PMID:Corticotropin-releasing hormone differentially modulates the interleukin-1 system according to the level of monocyte activation by endotoxin. 758 1

This study was undertaken to determine the effects of adrenomedullin (AM) on the secretion of cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 family, from lipopolysaccharide-stimulated rat alveolar macrophages in vitro. AM significantly increased cAMP levels in alveolar macrophages in a dose-dependent fashion. On the other hand, AM significantly inhibited CINC secretion from alveolar macrophages in a dose-dependent fashion, and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) also significantly inhibited CINC secretion. These findings suggest that AM may play important roles in the regulation of airway inflammation via a cAMP-dependent mechanism.
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PMID:Adrenomedullin inhibits the secretion of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, from rat alveolar macrophages. 759 89

Many functions of the immune and inflammatory responses are inhibited by agents that increase intracellular levels of cAMP. Recent investigations have revealed that cAMP levels in inflammatory cells are regulated by cyclic nucleotide phosphodiesterases (PDEs) belonging to the PDE4 family (cAMP-specific PDEs). At least four different genes are known to encode PDE4 isozymes, which are characterized by their selectivity for cAMP over cGMP and their sensitivity to the antidepressant drug rolipram. The aim of our studies was to investigate whether monocytic cells could regulate PDE4 activity and whether certain PDE4 isozymes were expressed preferentially over others. Our results showed that treatment of peripheral blood monocytes or closely related Mono Mac 6 cells with dibutyryl-cAMP or other cAMP-elevating agents transiently increased rolipram-sensitive PDE4 activity 2-3-fold, without concomitant increases in cGMP-inhibited PDE (PDE3) activity. PDE4 activity was predominantly cytosolic, whereas PDE3 activity was localized to the particulate fraction. Our Northern and Western blot studies with reagents recognizing three distinct PDE4 gene products (PDE4A, PDE4B, and PDE4D) revealed that their expression is transcriptionally regulated in monocytic cells. Although none of the three isozymes was detectable under normal culture conditions, all of these were up-regulated when Mono Mac 6 cells were exposed to dibutyryl-cAMP. Distinct differences were observed in their temporal patterns of expression. Endotoxin lipopolysaccharide, a potent monocyte stimulus, also enhanced PDE4 activity in monocytic cells. These data indicate that monocytic cells may express different PDE4 isozymes, depending on their state of activation or differentiation. These isozymes could thus regulate intracellular cAMP levels at various stages of monocyte activation and could thereby be important in limiting the inflammatory response.
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PMID:Regulation of distinct cyclic AMP-specific phosphodiesterase (phosphodiesterase type 4) isozymes in human monocytic cells. 760 56

The volatile sulphur compound methyl mercaptan (CH3SH) is a by-product of protein metabolism and a principal component of oral malodour. This investigation examines the effect of CH3SH on the enzymatic activities of cathepsins B and G and elastase, and on the production by human gingival fibroblasts of two key factors, prostaglandin E (PGE) and cAMP, of the PGE2-cAMP-dependent pathway, which may contribute to the increased production of collagenase and tissue destruction in human periodontal disease. The results demonstrate that CH3SH alone, or in combination with interleukin-1 (IL-1) or lipopolysaccharide, can significantly enhance the secretion of PGE2, cAMP and procollagenase by human gingival fibroblasts. CH3SH also stimulated mononuclear cells to produce IL-1, which can increase cAMP production, and act in synergism with the direct effect of CH3SH on cAMP. CH3SH also significantly enhanced the activity of cathepsin B, moderately suppressed that of cathepsin G, but did not significantly affect elastase. These results provide evidence that CH3SH could be a contributing factor in the enzymatic and immunological cascade of events leading to tissue degradation in periodontal diseases.
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PMID:Stimulation of enzyme and cytokine production by methyl mercaptan in human gingival fibroblast and monocyte cell cultures. 760 61

Epidermal Langerhans cells (LC) are associated anatomically with epidermal nerves, and a product of these nerves, calcitonin gene-related peptide (CGRP), inhibits the antigen-presenting capacity of LC and macrophages. As the CGRP receptor appears to be coupled to Gs alpha protein, which in turn activates adenylate cyclase, the ability of CGRP to induce cAMP in LC was examined and correlated with functional effects. LC were isolated from murine epidermal cells using antibodies on magnetic microspheres. Exposure to CGRP induced a significant increase in cAMP content, which could be inhibited by coculture with a truncated form of CGRP [CGRP-(8-37)] that is a specific competitive inhibitor of CGRP. Substance P and calcitonin failed to induce cAMP in LC. Although culture in CGRP reduced the ability of murine epidermal cells enriched for LC content to present pigeon cytochrome c to a responsive clone or to present antigen for elicitation of delayed-type hypersensitivity in immune mice, culture in forskolin had little or no effect on antigen presentation despite increased cAMP content of LC as much or more than that induced by CGRP. The effect of CGRP on antigen presentation in these systems could be blocked with CGRP-(8-37). CGRP inhibited the induction of B7-2 by lipopolysaccharide on peritoneal macrophages and a LC line, whereas calcitonin did not. CGRP induces specific accumulation of cAMP in LC and inhibits LC antigen-presenting function by a receptor-mediated event. However, the induction of cAMP by itself does not account for inhibition of antigen presentation. Suppression of the expression of B7-2 may be one mechanism by which CGRP inhibits antigen presentation.
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PMID:Specific induction of cAMP in Langerhans cells by calcitonin gene-related peptide: relevance to functional effects. 766 88

In the present study we examined the influence of FSH as well as a number of well-established cytokines on interleukin (IL)-6 by rat granulosa cells in culture. Increasing concentrations of FSH, IL-1 alpha, IL-1 beta, tumor necrosis factor alpha (TNF alpha), and lipopolysaccharide (LPS) were incubated for 48 h with undifferentiated granulosa cells obtained from diethylstilbestrol-primed immature rats. The results demonstrate that FSH, IL-1 alpha, IL-1 beta, and LPS, but not TNF alpha, caused significant concentration-dependent increases in IL-6 release. We also examined the effects of dibutyryl-cAMP, forskolin, and 3-isobutyl-1-methyl-xanthine (IBMX) on IL-6 release by granulosa cells. Each of these agents caused a significant concentration-dependent increase in IL-6 production by granulosa cells in either the absence or presence of FSH. Taken together, these results show that the granulosa cell is not only a likely source of IL-6 but that the release of IL-6 can be regulated. Moreover, evidence suggests that cAMP may serve as a second messenger for the stimulated secretion of IL-6 by undifferentiated granulosa cells.
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PMID:Interleukin-6 production by rat granulosa cells in vitro: effects of cytokines, follicle-stimulating hormone, and cyclic 3',5'-adenosine monophosphate. 768 Sep 7

Murine peritoneal macrophages primed in vivo by trehalose dimycolate (TDM) express cytostatic activity against tumor cells after treatment in vitro with 10 ng/ml lipopolysaccharide (LPS) during a 4-hr period (activation step). There is a strict correlation (P < 0.0001) between acquisition of antitumoral activity and induction of NO synthase quantified by its end products citrulline and NO2-. LPS also stimulates the release of cyclooxygenase products which exert a retroinhibitory action on NO synthase and cytostatic activities, as judged by an increase of both parameters by indomethacin (1 microM) and a decrease by externally added PGE2 (1 microM). LPS increases cellular and extracellular cAMP levels through an indomethacin-sensitive pathway, pointing to cAMP as a second messenger in the retroinhibitory action of LPS-induced prostaglandins. In fact, the addition of 8-bromo-cAMP or of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine during the activation step decreases NO synthase activity; however, at the same time these drugs increase the apparent efficiency of NO as an antitumor agent.
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PMID:LPS-induced activation of primed murine peritoneal macrophages is modulated by prostaglandins and cyclic nucleotides. 768 61


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