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)

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

Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulating ferritin. Four lines of evidence suggest that TNF-alpha regulates ferritin independently of iron. First, evaluation of mRNA showed that TNF-alpha increased ferritin H chain specifically, provoking no change in steady-state levels of ferritin L mRNA; iron, in contrast, increased the mRNA of both isoforms. Second, the increase in ferritin H protein synthesis observed during TNF-alpha treatment was dependent on an increase in ferritin H mRNA: actinomycin D blocked the TNF-alpha-induced changes in ferritin H but did not inhibit the translational induction of ferritin seen with iron treatment. Third, equal ferritin mRNA induction was observed in iron-loaded cells and in cells depleted of iron by a permeant chelator, 2,2'-dipyridyl. Fourth, ferritin H induction by TNF-alpha and iron was additive over the entire range of iron concentrations, even at TNF-alpha doses known to maximally stimulate ferritin H mRNA levels. Nonetheless, the role of iron in translational regulation of ferritin was retained in TNF-alpha-treated cells; effective biosynthesis of TNF-alpha-induced, H-subunit-predominant ferritin protein required iron and could be enhanced by treatment of the cells with additional iron or blocked by 2,2'-dipyridyl. Finally, we observed that the TNF-alpha-mediated increase in ferritin synthesis peaked at 8 hr and was followed by a decrease in both H and L isoferritin synthesis; the addition of iron, however, reversed the late-occurring depression in ferritin synthesis. This suggests that TNF-alpha-induced synthesis of H-rich ferritin may reduce the regulatory pool of intracellular iron, secondarily inhibiting iron-mediated translation of ferritin mRNA. We conclude that TNF-alpha acts independently of iron in its induction of ferritin H mRNA but requires the presence of iron for this effect to be fully expressed at the protein level.
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PMID:Iron-independent induction of ferritin H chain by tumor necrosis factor. 205 77

We report the cloning, expression and characterization of biologically active feline tumour necrosis factor-alpha (fTNF-alpha). Messenger RNA was extracted from feline peritoneal macrophage cultures and used to synthesize cDNA for polymerase chain reaction (PCR) amplification. The PCR products were cloned into the plasmid vector pCRII and sequenced, showing 99.3% homology with a published fTNF-alpha gene sequence. Subcloning into the vector pGEX-2T and subsequent expression resulted in a 43 kDa fusion protein of fTNF-alpha and glutathione S-transferase (GST). Thrombin cleavage of the fusion protein yielded a 17 kDa protein. This protein cross-reacted with a monoclonal anti-human TNF-alpha antibody in Western blotting, but not with a polyclonal anti-murine TNF-alpha serum. Recombinant fTNF-alpha (rfTNF-alpha) and rfTNF-alpha-GST had a CD50 of 15 ng ml-1 and 230 ng ml-1, respectively, in the L929 cytotoxicity assay. Cats given rfTNF-alpha-GST intravenously manifested the typical biological effects of TNF-alpha, including fever, depression, and piloerection. The rfTNF-alpha-GST upregulated IL-2 receptor and MHC-II antigen expression on peripheral blood mononuclear cells stimulated in vitro, but had no effect on TNF-alpha receptor and MHC-I antigen expression.
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PMID:Cloning, expression and characterization of biologically active feline tumour necrosis factor-alpha. 767 12

Inflammatory cells in lymph nodes of eighteen patients suffering from culture-proven tuberculous lymphadenitis were examined by histological and immunohistochemical techniques. Ten patients suffered from symptomatic HIV-infection and eight patients were immunocompetent individuals without HIV-1 serology. Characteristic granulomas with or without caseation were observed in eight immunocompetent and four HIV-1-infected patients with less marked lymphopenia of CD4 positive peripheral blood lymphocytes. No epitheloid cell formation was present in lymph nodes of HIV1-infected patients with more severe depression of CD4 positive peripheral blood lymphocyte count. Foamy macrophages were found instead of these cells. While many cells--predominantly lymphocytes--express CD25 (IL-2 receptor) in cases with typical epitheloid granulomas there is no such CD25 expression in cases without any epitheloid cell formation. This result suggest that T cell function is necessary for epitheloid granuloma formation in human tuberculosis. The phenotype of macrophages underwent progressive changes parallel to decreasing numbers of CD4 positive peripheral blood lymphocytes. Foamy macrophages in Mycobacterium avium-intracellulare infection represented an end-stage phenotype. They were positive for S100 protein and they did not express lysozyme, alpha-1-anti-chymotrypsin, L1 antigen (Mac387) and CD4, whereas positivity for HLA-DR, CD68 and Ki-M8 was preserved. In situ immunohistochemical demonstration of IFN-alpha, IFN-beta, TNF-alpha, IL-1 and IL-6 revealed that foamy cells in M. tuberculosis infection were highly active effector cells. They contained higher concentrations of the examined cytokines than epitheloid cells in the lesions of HIV+ and HIV-patients. Corresponding to these findings the histological proof of acid-fast bacilli was generally not successful in typical HIV-associated tuberculosis. The foamy appearance may result from the lipid-rich cell membranes of destroyed acid-fast bacilli. In contrast acid-fast bacilli-packed foamy macrophages in AIDS patients with M. avium-intracellulare (MAI) infection did not produce any of the examined cytokines.
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PMID:Immunohistochemical analysis of cell composition and in situ cytokine expression in HIV- and non-HIV-associated tuberculous lymphadenitis. 771 49

Acute Plasmodium yoelii murine malaria is associated with a marked depression of splenic T cell responses. The present study was undertaken to address the question if a defect in T cell proliferation results from a relative increase of a non-T cell population in the spleen or real biological changes occurring in T cells of the spleen after infection. When animals were acutely infected, the splenic cells responded poorly to cross-linked anti-CD3 mAb, Con A, and PWM stimulation. At this stage, a very limited array of cytokine was expressed. We failed to detect the transcripts for IL-2R p55, IL-2, IL-6, IL-10, and IFN-gamma in mice with acute P. yoelii malaria irrespective of the number of splenocytes subjected to RT-PCR. In contrast, late in the infection when mice cleared the parasites and became resistant to reinfection, mRNAs for the above cytokines as well as for IL-4, IL-5, GM-CSF, and TNF-alpha were detectable. During this late phase of infection, lymphocytes proliferated vigorously in response to TCR- and T cell mitogen-mediated stimulation. Surprisingly, during an early phase (as early as 3 days postinfection) with low parasitemia, before the establishment of T cell unresponsiveness, a broad array of cytokine expression including IL-2 and IFN-gamma expression as well as marked lymphoproliferative response upon T cell mitogen- and TCR-mediated stimulation was observed. When the expression of cytokine gene in freshly isolated (ex vivo) splenocytes from P. yoelii-infected animals was investigated, a similar pattern of cytokine profile was detected. We devised a methodology in which RNA from an increasing number of splenocytes (ranging from 1 to 16 million) was used to compensate for any difference in the frequency of splenic T cells between immune and acutely infected mice and to augment target molecules which could be measured simultaneously by PCR. The data presented in this study led us to speculate that "anergy" or relative increase of a non-T cell population cannot account solely for the T cell unresponsiveness in the acute phase of infection. We suggest that inactivation or/and ablation of reactive T cells may explain T cell hyporesponsiveness during acute malaria.
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PMID:Plasmodium yoelii in mice: differential induction of cytokine gene expression during hyporesponsiveness induction and restimulation. 784 88

Using animal models or healthy volunteers, injection of lipopolysaccharide (LPS) or bacteria causes activation of macrophages with excessive synthesis and secretion of proinflammatory cytokines. Although these models mimic the effects of LPS in the host, they may represent more of an experimental expression of endotoxemia than natural infection itself. Therefore, as an ex vivo model of sepsis, whole blood from 15 patients with severe sepsis and 20 control patients without infection was stimulated with LPS to study the kinetics of mRNA expression and release of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6. Stimulation of whole blood with 1 microgram/mL LPS resulted in a maximum increase of cytokine secretion in the control group, while a marked (P < .01) depression of TNF-alpha, IL-1 beta, and IL-6 release was observed in the septic group, which persisted up to 10 days after study enrollment. While IL-1 beta mRNA expression was similar in peripheral blood mononuclear cells (PBMCs) harvested from LPS-stimulated whole blood in septic and control patients, the half-life and consequently the expression of TNF-alpha and IL-6 mRNA were strongly reduced in the septic group. These data indicate a downregulatory mechanism of cytokine release in whole blood from patients with severe sepsis that occurs on different levels. Although excessive secretion of proinflammatory cytokines has been considered deleterious for the host, the reduced capacity of PBMCs in whole blood from septic patients to synthesize and secrete proinflammatory cytokines to an inflammatory stimulus may result in immunodeficiency, because these cytokines in low concentrations are involved in the upregulation of essential cellular and humoral immune functions.
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PMID:Downregulation of proinflammatory cytokine release in whole blood from septic patients. 785 64

Acute lung injury, characterized as the adult respiratory distress syndrome (ARDS), is a common clinical occurrence following blood loss and injury. We previously found increased levels of transforming growth factor (TGF)-beta 1 mRNA in murine intraparenchymal mononuclear cells and in alveolar macrophages within 1 h after hemorrhage. Because TGF-beta has potent proinflammatory and immunoregulatory properties, we investigated the effect of blocking TGF-beta with mAb on hemorrhage-induced pathology, cytokine mRNA levels in lungs, as well as survival from pneumonia. Mice treated with anti-TGF-beta mAb showed normal pulmonary histology 3 days after hemorrhage and resuscitation in contrast to the mononuclear and neutrophil infiltrates, intraalveolar hemorrhage, and interstitial edema found in hemorrhaged mice either treated with control antibody or not treated with any antibody. Decreased mRNA levels for IL-1 beta, TNF-alpha, IL-6, IL-10, and IFN-gamma as compared with untreated, hemorrhaged controls were present in intraparenchymal pulmonary mononuclear cells following therapy with anti-TGF-beta. In contrast, therapy with anti-TGF-beta increased mRNA levels for IL-1 beta and TNF-alpha in alveolar macrophages and for TGF-beta in peripheral blood mononuclear cells collected 3 days after hemorrhage. Administration of anti-TGF-beta to hemorrhaged mice did not correct the enhanced susceptibility to Pseudomonas aeruginosa pneumonia that exists after hemorrhage. These results suggest that TGF-beta has an important role in hemorrhage-induced acute lung injury, but does not contribute to the post-hemorrhage depression in pulmonary antibacterial response.
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PMID:Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice. 808 71

Iron influences host immunity, in part by affecting the function and migration patterns of T cell subpopulations. Removal of iron stores from the body by chelation decreases proliferation and differentiation of T cells, as shown in models of autoimmunity and pancreatic islet transplantation. We have examined the influence of iron chelation on rejection of vascularized heart allografts in rats. Two protocols were investigated: "treated" recipients received desferrithiocin (30 mg/kg/day) orally for 10 days beginning the day of transplantation; "pretreated" hosts received a similar dose of the drug for 10 days before engraftment. Graft survival increased from about 7 days in untreated animals to 14-16 days in both treatment groups (P < 0.001). Histological and immunoperoxidase studies of allografts at day 7 showed that iron chelation resulted in only a mild reduction in cell infiltration, but in a marked decrease in graft edema and interstitial hemorrhage and essentially complete suppression of mononuclear cell activation and cytokine production. Chelation therapy was also found to inhibit profoundly cytokine (TNF-alpha) production in rats treated with LPS, consistent with the effects observed in situ in the allografts. In vitro studies showed that pretreatment significantly inhibited the mixed lymphocyte reaction. Chelation also influenced migration of T lymphocyte subsets: treatment stimulated migration of CD4+ lymphocytes to peripheral lymph nodes; pretreatment strikingly and selectively increased CD8+ cell migration into parathymic lymph nodes draining the graft, with the opposite effect on nondraining node groups. We conclude that treatment with iron-chelating agents has several effects on host alloresponsiveness in a rat heart graft model secondary to inhibition of immune activation; these include prolongation of graft survival, inhibition of the mixed lymphocyte reaction (pretreatment), marked depression of cytokine production, and alteration in recirculation patterns of lymphocyte subpopulations.
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PMID:Iron chelation suppresses mononuclear cell activation, modifies lymphocyte migration patterns, and prolongs rat cardiac allograft survival in rats. 824 21

The production of the cytokines IFN-gamma, IL-1-alpha, IL-2 and TNF-alpha was investigated in mitogen-stimulated, whole blood cell culture from 239 untreated patients with primary gynaecological carcinomas (breast, cervix, ovary, endometrium), and 191 healthy female controls. The cytokines were measured in the 4-day post-induction supernatants by a sensitive enzymoimmunological assay. In the blood cell cultures of all four groups of cancer patients, significantly lower values of IFN-gamma (P < or = 0.001), IL-2 (P < or = 0.01) and IL-1 alpha (P < or = 0.01) were found as compared to the controls, although lymphocyte and monocyte counts were almost identical. Grouping the tumour patients into different clinical stages we could show in the four groups of carcinomas a gradual depression of the cytokine production according to growing tumour burden.
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PMID:Impaired cytokine production in whole blood cell cultures of patients with gynaecological carcinomas in different clinical stages. 831 18

Although plasma levels of tumor necrosis factor (TNF) are elevated and hepatocellular dysfunction occurs even in the early hyperdynamic stage of sepsis, the precise mechanism responsible for this dysfunction remains unknown. Although TNF at high doses produces circulatory failure, it is not known whether the dose of TNF that does not adversely affect hemodynamics alters hepatocellular function. To study this, recombinant murine TNF-alpha was infused intravenously (0.05 or 0.25 mg/kg) over 30 min in normal rats. At 1 and 4 h after infusion of TNF-alpha or an equivalent volume of saline, hepatocellular function [i.e., maximum velocity (Vmax) and Michaelis constant (Km)] was assessed using in vivo indocyanine green clearance without blood sampling. Additional parameters measured were as follows: cardiac output by dye dilution, hepatic microcirculation by laser Doppler flowmetry and colloidal carbon infusion, plasma TNF and interleukin-6 (IL-6) by cytokine-dependent cellular assays, and plasma glucose enzymatically. The results indicate that although infusion of 0.05 mg/kg TNF-alpha did not affect Vmax and Km, its infusion at 0.25 mg/kg produced a significant depression of hepatocellular function and markedly increased the synthesis and/or release of IL-6. TNF-alpha-induced hepatocellular dysfunction was not associated with any significant changes in hepatic microcirculation, plasma glucose, cardiac output, and other measured hemodynamic parameters. Thus hepatocellular dysfunction observed after TNF infusion may be due to the direct effect of this cytokine alone or in combination with IL-6.
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PMID:Tumor necrosis factor-alpha produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation. 820 42


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