Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the acute-phase response to bacterial endotoxins [lipopolysaccharide (LPS)] in mice, the hepatic activity of haem oxygenase (HO) is increased. We investigated the effects of the potential humoral mediators of inflammation, interleukin-1 (IL-1) and tumour necrosis factor (TNF), on hepatic HO activity. In mice, IL-1 or TNF (5 micrograms) caused an elevation of HO activity comparable with that after LPS exposure (20 micrograms). The induction of HO by both cytokines was more pronounced in adrenalectomized mice. In the intact mice induction of HO activity by cytokines was observed earlier than depression of 7-ethoxycoumarin O-de-ethylase, a cytochrome P-450-dependent enzyme activity. Pretreatment with dexamethasone of the intact mice (3 mg/kg) or of the adrenalectomized mice (0.4 mg/kg) prevented the induction of HO activity caused by LPS and IL-1 respectively. These results suggest that: (1) HO activity is increased during an IL-1- or TNF-mediated acute-phase response, so haem metabolism might be a potential target of inflammation, and (2) HO induction by IL-1 and TNF does not require glucocorticoids, which in fact act as antagonists of this cytokine-induced effect.
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PMID:Interleukin-1 and tumour necrosis factor induce hepatic haem oxygenase. Feedback regulation by glucocorticoids. 183 80

Despite continuous exposure to gut-derived endotoxin (lipopolysaccharide) under normal conditions, Kupffer cells (KC) fail to generate detrimental cytokine responses. KC function within a unique microenvironment in which high hepatic arginase activities (25 times greater than those activities in the kidney) result in negligible local L-arginine levels. To evaluate the relevance of this profound arginine deficiency on the physiologic function of KC, the kinetics of tumor necrosis factor (TNF-alpha) production and autoregulatory eicosanoid prostaglandin E2 (PGE2) production were compared in lipopolysaccharide-stimulated KC cultured with (1200 mumol/L) and without (10 mumol/L) L-arginine media. In (+)arginine culture the KC TNF-alpha production peaked early before decreasing as PGE2 production increased. In (-)arginine culture, however, KC TNF-alpha production was significantly (p less than 0.01) reduced, whereas PGE2 production was amplified (p less than 0.01). When cyclooxygenase blockade with indomethacin completely prevented KC production of PGE2 in (-)arginine culture, TNF-alpha production was upregulated (p less than 0.001 vs (-)arginine; p not significant vs (+)arginine). These arginine-specific depression of TNF-alpha responses appeared unique to KC because both TNF-alpha and PGE2 levels increased when peritoneal, pleural, and alveolar macrophages were stimulated by lipopolysaccharide in (-)arginine medium. This PGE2-dependent autoregulation of potentially harmful lipopolysaccharide-induced TNF-alpha responses may reflect an evolutionary adaptation by KC to their local hepatic environment and strategic anatomic position in the portal circuit, which optimally removes endotoxin and naturally protects the host.
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PMID:A biologic basis for limited Kupffer cell reactivity to portal-derived endotoxin. 185 31

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre-IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.
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PMID:Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha. 186 53

For many years tuberculosis has been known to occur with greater frequency among persons with disorders that impair host defenses. In most instances these processes interfere with the immune response to Mycobacterium tuberculosis, whereas, in a few, such as silicosis, the probable abnormality is a nonimmune defect in macrophage function. Infection with the human immunodeficiency virus (HIV) causes progressive and ultimately profound depression of both humoral and cell-mediated immunity and, thus, is an extremely potent risk-factor for tuberculosis. Presumably the major effect of HIV infection that predisposes persons to developing tuberculosis is the reduction in circulating T-helper (CD4+) lymphocytes which causes a reduction in cytokine production and a consequent decrease in the functional capabilities of macrophages. However, a number of questions concerning pathogenesis of tuberculosis related to HIV remain. Available data suggest that the magnitude of the risk for developing tuberculosis among persons infected with both HIV and M. tuberculosis is very high, 8% in one prospective study. Because of the epidemic of HIV infection, the progressive downward trend in the incidence of tuberculosis in the United States has reversed and in 1989 there was a 5% increase in the number of cases. Preliminary data for 1990 suggest that there will be an 8 to 10% increase over 1989. Also in the United States approximately 3% of tuberculosis patients have been found to be HIV seropositive. The clinical features of tuberculosis in patients with HIV infection vary depending on the degree of immunosuppression. With mild immunosuppression early in the course of HIV infection tuberculosis presents in a "typical" way with positive tuberculin skin tests, upper lobe cavitary infiltrates on chest film and positive sputum smears and cultures. As the HIV infection progresses, the mode of presentation of tuberculosis becomes more "atypical" with negative skin tests, multiple sites of involvement, chest films showing diffuse noncavitary infiltrates often accompanied by intrathoracic lymphadenopathy. The key to diagnosis is maintaining a high index of suspicion for tuberculosis, especially in patients with advanced HIV disease and including appropriate laboratory examinations in the evaluations of such persons. Regardless of the stage of HIV infection the response to treatment for tuberculosis is generally favorable if it is begun promptly. Standard therapy utilizing isoniazid, rifampin, and pyrazinamide with or without ethambutol have been associated with high rates of cure. Relapse has been uncommon. There has been, however, at least one outbreak of tuberculosis caused by isoniazid and rifampin resistant organisms in which the response to therapy was very poor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clinical features, diagnoses, and management of tuberculosis in immunocompromised hosts. 194 27

Chronic Graft-versus-Host disease (GVHD) is characterized by overt immunosuppression. In addition, the skin is a major anatomical site affected in chronic GVHD for reasons not yet known. Increased collagen deposition, a mononuclear cell infiltrate in the dermis as well as loss of fat and appendages, are observed in the skin. The inflammatory cytokine IL-1 was shown to affect fibroblast proliferation and secretory activities. In the present study, IL-1 generation by dermal fibroblasts, of chronic GVHD or control mice, was assessed. It was shown that two sequential signals are needed for IL-1 generation by dermal fibroblasts; priming by lymphokines/cytokines followed by a challenge with LPS. A variety of recombinant lymphokines and cytokines (G/M-CSF, IL-2, TNF, IL-1 beta and IFNs alpha, beta and gamma) were shown to be efficient in priming dermal fibroblasts for IL-1 generation. IL-1 activity in dermal fibroblasts, most probably of the IL-1 alpha species, was located in frozen-thawed cell lysates or associated to the cell membrane, though not secreted into the culture fluids. Dermal fibroblasts from chronic GVHD mice manifested a pronounced depression in IL-1 generation upon stimulation with exogenous lymphokines/cytokines and LPS. This was observed over a wide range of concentrations of lymphokines/cytokines and LPS. The depressed ability of chronic GVHD fibroblasts to generate IL-1 was pronounced even after few passages of the cells in vitro, and upon stimulation in culture outside the suppressive milieu of the animal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Depressed IL-1 production by chronic GVHD dermal fibroblasts. 210 13

We have investigated the effects of interleukin 1 (IL-1) administration on the ability of neutropenic mice to resist Pseudomonas aeruginosa challenge in vivo. Cyclophosphamide-treated mice received human rIL-1 beta at 7.0, 0.7, or 00.7 micrograms/kg, according to different regimens, to be challenged with a lethal ip inoculum of pseudomonas cells 5 days after myelosuppression. The repeated exposure of the neutropenic mice to an overall cytokine dosage of 7.0 or 0.7 micrograms/kg during the 4 days after myelosuppression was found to optimally restore the animals' antibacterial resistance. However, when administered as a single injection 24 hr before challenge, the same dosages of IL-1 had lower or no effect in enhancing survival, primarily leading only to a reduction in the amount of antipseudomonal chemotherapy required for cure. The regimen of IL-1 administration conferring optimal protection also resulted in a decrease in the number of pseudomonas cells recovered from the peritoneal cavity of infected mice. This regimen accelerated hematopoietic recovery in cyclophosphamide-treated mice. Assay of serum colony-stimulating activity (CSA) revealed that (a) cyclophosphamide treatment alone significantly increased the level of circulating CSA, (b) administration of a single dose of IL-1 to neutropenic mice induced an early, further increase in serum CSA, followed by depression, (c) a biphasic pattern of CSA response was also evident in mice repeatedly treated with IL-1. These results suggest that regulation of hematopoiesis may have an important role in the induction of antibacterial resistance in myelosuppressed hosts repeatedly treated with low dosages of IL-1.
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PMID:Antibacterial resistance induced by recombinant interleukin 1 in myelosuppressed mice: effect of treatment schedule and correlation with colony-stimulating activity in the bloodstream. 211 38

Interleukin 1 (IL 1) production is stimulated by infection, cellular injury, and inflammation. This cytokine directs a wide spectrum of host responses. Human interleukin 1 alpha (IL 1 alpha) was used to examine the time course of effects on zinc metabolism as part of the acute phase response. IL 1 produced a transient depression in the serum zinc concentration and increased serum ceruloplasmin. Metallothionein levels were increased in liver 14-fold after IL 1. Increased expression of metallothionein-1 and -2 genes following IL 1 were observed in liver, bone marrow, and thymus. Pulse-labeling experiments with i.v.-administered 65Zn showed that IL 1 drastically altered zinc distribution kinetics among tissues. More 65Zn was taken up (and/or retained) by the liver, bone marrow, and thymus 6 h after IL 1, whereas correspondingly less 65Zn was found in bone, skin, and intestine. Uptake by other tissues was not affected by IL 1. Chromatography of cytosol from tissues with increased 65Zn uptake suggests the IL 1-induced redistribution may be driven by enhanced metallothionein synthesis. Collectively, the results show that IL 1 regulates zinc metabolism and may direct its preferential, tissue-specific distribution via elevated metallothionein-1 and -2 gene expression.
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PMID:Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. 245 83

Many types of shock are characterized by profound hemodynamic alterations and depression of immune processes. Among the various mediators implicated in shock conditions, there is much evidence to suggest that, together with various cytokines, the inflammatory and chemotactic autacoid, platelet-activating factor (PAF), plays an important role. Studies on several animal models have shown that infusion of PAF mimicks the shock state, that markedly increased levels of PAF are produced in shock and that PAF antagonists afford significant protection against diverse forms of shock. The precise mechanism by which PAF antagonists protect against shock remains unclear; however, it is becoming apparent that in traumatic states a complex interaction occurs between PAF and cytokines, which leads to the acute phase reaction and circulatory collapse. We propose that PAF antagonists may be effective in counteracting shock because of their antiprotease activity and their ability to inhibit deleterious PAF/cytokine auto-generated feedback processes.
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PMID:Platelet-activating factor and cytokine interactions in shock. 255 74

The cytotoxic mechanism of action of tumor necrosis factor (TNF) was examined using murine L929 fibrosarcoma cells in vitro. Two cell lines were evaluated: parental TNF sensitive (L929S) (50% cytotoxic concentration, 2-6 ng/ml); and TNF resistant (L929R) (50% cytotoxic concentration, greater than 10,000 ng/ml). The latter resistant cell line was developed by serial passage in increasing concentrations of recombinant human TNF. Sensitive cells demonstrated cytolytic and cytostatic effects at TNF concentrations between 2 and 6 ng/ml, respectively. However, TNF failed to show any selective depression of RNA, DNA, or protein synthesis or ATP content in these cells until general cell death was apparent, as defined by the cell rounding and lifting off the plastic surface. The cytokine also failed to cause DNA single-strand breaks, as detected by alkaline elution techniques. TNF was also found to be no more active in glutathione-depleted cells than in target cells containing normal glutathione levels. In contrast, various nonspecific lysosomotropic agents such as ammonium chloride and D-saccharic acid lactone led to a marked inhibition of the cytotoxic action of TNF in vitro. Furthermore, significant differences in lysosomal enzyme activity were noted between L929S and L929R cells. The changes in L929R cells involved a 50% reduction in total lysosomal protein levels and a marked depression of beta-glucuronidase activity. In contrast, L929R lysosomal hexosaminidase activity was significantly elevated over the L929S cells. From these studies it is concluded that the antitumor activity of TNF does not involve specific inhibition of macromolecular synthesis, ATP production, or the level of reduced thiols. Instead, TNF cytotoxicity appears to require functional lysosomes, which are altered when TNF resistance develops in vitro.
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PMID:Association of lysosomal activity with sensitivity and resistance to tumor necrosis factor in murine L929 cells. 271 56

We hypothesize that reversible depression of cardiac function in cardiac allograft rejection and lymphocytic myocarditis reflects down modulation of the beta-adrenergic receptor system by a soluble product of activated immune cells. Thus, exposure of cultured cardiac myocytes to mixed lymphocyte culture or activated splenocyte supernatants produces 70% inhibition of isoproterenol-stimulated cAMP concentrations (Ki = 5% supernatant) in the absence of gross cellular injury or control media effects. This cAMP suppressive factor is not dialyzable and is ammonium sulfate precipitable. Beta-adrenergic receptor density, binding constant and affinity states are unaffected. These results demonstrate the existence of a cytokine inhibitor of cAMP accumulation that may mediate, in part, depression of cardiac contractility observed when immune cells invade the myocardium.
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PMID:Immune cytokine inhibition of beta-adrenergic agonist stimulated cyclic AMP generation in cardiac myocytes. 282 59


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