Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:009512 (tumor necrosis factor)
 58,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-4 has been implicated in the pathogenesis of leishmaniasis in a murine model. Experiments were done to examine the effect of IL-4 on cytokine activation of macrophages. Interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF alpha), and IL-3 activate macrophages to inhibit replication of leishmaniae. IL-4 abrogated in a dose- and time-dependent manner the induction of antileishmanial activity by these cytokines. The depression of oxidative burst capacity is one mechanism by which IL-4 inhibits macrophage activation. IL-4 diminished in a dose- and time-dependent manner the TNF alpha enhancement of oxidative capacity. Pretreatment with IL-4 for 48, 24, or 0 h, respectively, inhibited the generation of superoxide induced by TNF alpha by 90%, 60%, and 40%. Furthermore, IL-4 abrogated the enhancement of oxidative capacity by IFN-gamma, GM-CSF, and IL-3. These data suggest that IL-4 is a potent deactivator of macrophage antimicrobial functions and may contribute to the pathogenesis of visceral leishmaniasis.
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PMID:Interleukin-4 inhibits human macrophage activation by tumor necrosis factor, granulocyte-monocyte colony-stimulating factor, and interleukin-3 for antileishmanial activity and oxidative burst capacity. 130 48

Prenatal exposure to benzodiazepines (BDZ) can cause behavioral dysfunctions both in humans and in experimental animals. In addition, prolonged impairment of cellular immune functions is found in rats after low dose BDZ exposure (e.g., diazepam 1.25 mg/kg/day) during part of fetal life [gestational days (GD) 14-20]. Analysis of diazepam and its metabolites in maternal and fetal tissues revealed that in this rat model the drug is no longer present at birth, which excludes direct effects of diazepam during the postnatal period. The main target of BDZ in brain, the GABAA receptor complex, is structurally and functionally heterogeneous. Besides alpha- and beta-subunits, gamma 2- or gamma 3-subunit should be coexpressed for a fully functional BDZ response. Signals of mRNAs encoding for alpha 1, beta 2 and gamma 2 are detected in fetal rat spinal cord and lower brainstem by GD 14 and reach telencephalic regions in later fetal life, reminiscent of BDZ receptor ontogeny. Regional subunit distribution differs from the adult brain, one interesting feature being a preponderance of gamma 2 mRNA throughout fetal life. Since subunit composition influences the sensitivity to BDZ, these data suggest that prenatal effects of BDZ depend upon regional subunit compositions present at different developmental stages. The delayed depression of cellular immune responses in prenatally BDZ-exposed rat offspring during the first 2 postnatal months is accompanied by various changes in immune cell biology. Binding characteristics of the peripheral (omega 3) type BDZ receptor are altered until adulthood (8 weeks). Membranes of spleen cell preparations containing mainly lymphocytes exhibit a decrease of affinity for the peripheral ligand [3H]PK11195, splenic macrophage preparations a decrease of maximal binding capacity. Various defects in cytokine production by macrophages and T lymphocytes were observed: Mitogen-stimulated release of macrophage-derived tumor necrosis factor-alpha (TNF-alpha) and of the T cell-derived interleukin-2 (IL-2) was drastically reduced at 2 and 4 weeks of life and recovered in young adulthood, exhibiting the same time course of depression as lymphocyte proliferation in response to immune stimuli. Interleukin-6 (IL-6) release remained diminished until adulthood. In female offspring, additional alterations were found in splenic noradrenaline turnover after immune stimulation. The mechanisms underlying the breakdown of the cytokine network in prenatally diazepam-exposed offspring, and the long-term consequences are as yet unknown.
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PMID:Nervous and immune systems as targets for developmental effects of benzodiazepines. A review of recent studies. 133 33

Since the discovery that interferon inducers depress hepatic drug metabolism, the depressant action of cytochrome P450 (P450) has been demonstrated to be shared by cytokines such as interferon alpha/beta and interferon gamma as well as interleukin-1 and tumor necrosis factor. Because these cytokines are inflammatory mediators, it is not surprising that theophylline toxicity has been reported in patients with influenza B epidemic. Hence, to lay a foundation for studies of altered steroid and drug metabolism, the alteration of P450 isozymes was studied after polyriboinosinic acid:polyribocitidylic acid (poly I:poly C) administration. Twenty-four hours after poly I:poly C administration, hepatic P450 content decreased to 57% of control, whereas depression of other microsomal enzymes was less pronounced: P450 reductase (69%), cytochrome b5 (74%) and NADH-cytochrome b5 reductase (85%). The depression of mRNA for cytochrome P450 1A1, 1A2, 2C11 and 2E1 was more than 60% of the controls. Recovery of mRNA levels was not complete within 72 hr. The changes in mRNAs, in general, paralleled alterations of monooxygenase activities and P450 isozyme content suggesting that the effect of poly I:poly C is pretranslational for all P450 isozymes studied. No overt differential effect on P450 isozymes was found after an administration of poly I:poly C. This study complements the previous report which demonstrated down-regulation of mRNA for cytochrome P450 2C11 and 3A2.
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PMID:Suppression of hepatic drug metabolism by the interferon inducer, polyriboinosinic acid:polyribocitidylic acid. 140

The influence of cytokines on extracellular superoxide dismutase (EC-SOD) expression by human dermal fibroblasts was investigated. The expression was markedly stimulated by interferon-gamma (IFN-gamma), was varying between fibroblast lines stimulated or depressed by interleukin-1 alpha (IL-1 alpha), was intermediately depressed by tumor necrosis factor-alpha (TNF-alpha), and markedly depressed by transforming growth factor-beta (TGF-beta). TNF-alpha, however, enhanced the stimulation by a high dose of IFN-gamma, whereas TGF-beta markedly depressed the stimulations given by IFN-gamma and IL-1 alpha. The ratio between the maximal stimulation and depression observed was around 30-fold. The responses were generally slow and developed over periods of several days. There were no effects of IFN-alpha, IL-2, IL-3, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, human growth hormone, Escherichia coli lipopolysaccharide, leukotriene B4, prostaglandin E2, formylmethionylleucylphenylalanine, platelet-activating factor, and indomethacin. The cytokines influencing the EC-SOD expression are also known to influence superoxide production by leukocytes and other cell types, and the EC-SOD response pattern is roughly compatible with the notion that its function is to protect cells against extracellular superoxide radicals. The results show that EC-SOD is a participant in the complex inflammatory response orchestrated by cytokines. The CuZn-SOD activity of the fibroblasts was not influenced by any of the cytokines, whereas the Mn-SOD activity was depressed by TGF-beta. TNF-alpha, IL-1 alpha, and IFN-gamma stimulated the Mn-SOD activity, as previously known, and these responses were reduced by TGF-beta. The different responses of the three SOD isoenzymes illustrate their different physiological roles.
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PMID:Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts. 155 78

Acidic sulfate is the most toxicologically important sulfur oxide which exists in the ambient air. To determine if particle size influences toxic effects of sulfuric acid, we investigated the effects of sulfuric acid aerosols of two different sizes on biochemical and cellular parameters of bronchoalveolar lavage fluid from exposed guinea pigs. Guinea pigs were exposed to fine (mass median diameter, 0.3 micron), and ultrafine (mass median diameter, 0.04 micron) sulfuric acid aerosols at 300 micrograms/m3 for 3 hr/day. The animals were euthanized immediately and 24 hr after 1 and 4 days of exposure and lungs were lavaged. Elevated beta-glucuronidase, lactate dehydrogenase activities, and total protein concentration as well as decreased cell viability were observed in the lavage after a single exposure to sulfuric acid aerosols of both sizes. These alterations were small, though statistically significant, and transient. No alteration in these parameters was observed after 4 days of exposure to acid aerosols. In contrast, sulfuric acid-induced alterations in alveolar macrophage function were more pronounced and longer lasting. Immediately after a single exposure to fine acid, there was a 2.7-fold increase in the spontaneous tumor necrosis factor (TNF) release over that in the control group while endotoxin-stimulated TNF release was increased by 2.2-fold. In addition, acid aerosols of both sizes increased the TNF release from macrophages after 4 days of exposure, although there was no clear temporal pattern of induction or recovery. Furthermore, immediately after 4 days of exposure to either fine or ultrafine acid, the amount of H2O2 that could be induced from baseline production by alveolar macrophages was 2.2-fold higher than that of the controls. The phagocytic function of macrophages was also altered by exposure to sulfuric acid aerosols. Twenty-four hours after single or multiple exposure, fine acid enhanced (as high as 78% above control) the in vitro phagocytic activity of alveolar macrophages while ultrafine acid depressed the phagocytic capacity (as much as 50% below that in the control). In addition to these biochemical parameters and cellular functions, we also measured the intracellular pH (pHi) of macrophages harvested after exposures to these acid aerosols using a pH-sensitive fluorescent dye. The resting pHi was depressed after a single exposure to both acid aerosols. The depression in pHi persisted 24 hr after ultrafine acid exposure.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of fine and ultrafine sulfuric acid aerosols in guinea pigs: alterations in alveolar macrophage function and intracellular pH. 155 43

Prostacyclin and beraprost sodium (beraprost), a stable analogue of prostacyclin, increased cyclic AMP (cAMP) levels of cultured human umbilical vein endothelial cells (HUVEC) in a concentration-dependent manner. The elevation of cAMP by beraprost was sustained longer than that by prostacyclin. The expression of thrombomodulin (TM) on membrane surface of HUVEC was enhanced by beraprost and prostacyclin, and the persistence of the increase in TM expression by beraprost was greater than prostacyclin. Dibutyryl cAMP (db-cAMP) mimicked the effects of beraprost and 3-isobutyl-1-methylxanthine enhanced the effects. Beraprost, prostacyclin and db-cAMP also effectively blocked the interleukin-1- and tumor necrosis factor-induced depression of TM expression substantially. These results suggest that TM expression is positively regulated by cAMP in HUVEC, and that beraprost may be potentially effective for reducing thrombotic events through the mechanism which initiates the stimulation of cAMP/TM system in vascular endothelial cells.
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PMID:Enhancement by beraprost sodium, a stable analogue of prostacyclin, in thrombomodulin expression on membrane surface of cultured vascular endothelial cells via increase in cyclic AMP level. 170 20

Although it is known that interferon-gamma synthesis and macrophage functions are depressed after hemorrhage, it remains to be determined whether systemic administration of interferon-gamma has any effect on hemorrhage-induced depression of macrophage and splenocyte functions. To study this, C3H/HEN mice were bled to a mean blood pressure of 35 mm Hg, maintained for 60 minutes, and followed by adequate fluid resuscitation. The mice then received either 1000 units interferon-gamma or saline solution (vehicle). Peritoneal (pM phi) and splenic (sM phi) macrophages and splenocytes were isolated 24 hours later. PM phi antigen presentation was measured by coculturing pM phi with the D10.G4.1 cell clone. Major histocompatibility complex class II (Ia) antigen expression was determined by direct immunofluorescence. Cytokine release by pM phi, sM phi, and splenocytes was assessed with specific bioassays. For survival studies, mice were subjected to sepsis 3 days after hemorrhage. Treatment with interferon-gamma restored (p less than or equal to 0.05) hemorrhage-induced suppression of pM phi antigen presentation capacity and Ia antigen expression and increased (p less than or equal to 0.05) interleukin-1 and tumor necrosis factor release by pM phi and sM phi, as well as splenocyte proliferation (p less than or equal to 0.05). Interferon-gamma also decreased (p less than or equal to 0.007) the susceptibility to sepsis after hemorrhage. Thus interferon-gamma represents a potent agent for treating hemorrhagic shock-induced immunosuppression and for increasing the ability of the host defense system to combat bacterial infections after hemorrhage.
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PMID:Interferon-gamma attenuates hemorrhage-induced suppression of macrophage and splenocyte functions and decreases susceptibility to sepsis. 173 88

We compared the early and late pulmonary effects of human recombinant tumor necrosis factor (TNF) and interleukin 1 (IL-1) challenges in awake dogs with chronic tracheostomies. Serial blood gas analysis, bronchoalveolar lavage (BAL) with cell and protein analysis, intravascular catheter hemodynamics, and radionuclide left ventricular ejection fractions (LVEF) were determined before and after infusion of TNF (60 micrograms/kg body wt, n = 8), IL-1 (1,000 micrograms/kg body wt, n = 6), or heat-inactivated IL-1 (n = 6, controls). Controls given heat-inactivated IL-1 had no changes (P = NS) in any pulmonary parameter throughout the study. Animals given IL-1 had a transient increase (P less than 0.05) in BAL neutrophil concentration 1 day after infusion but no other changes (P = NS) in pulmonary function throughout the study. Animals given TNF had early (0-4 h) decreases (P less than 0.05) in arterial PO2, increases (P less than 0.05) in physiological shunt fraction and alveolar-to-arterial PO2 gradient, and a high mortality rate (50%). In TNF animals, volume challenges at 4 h were associated (P less than 0.05) with death and noncardiogenic pulmonary edema. In TNF survivors, hypoxemia persisted for 2-3 days and was associated with increases (P less than 0.05) in alveolar protein and neutrophil concentration on days 1 and 3, respectively, which in survivors returned to near normal over 6-21 days. Animals challenged with TNF and not IL-1 had reversible depression of LVEF similar in time course to abnormalities in arterial PO2. In this study, TNF (but not IL-1) challenges were lethal and produced acute pulmonary dysfunction sustained over days (reversible in survivors) that was similar to that seen in human septic shock. The ability of TNF to induce pulmonary injury similar to bacterial shock suggests that TNF is a key mediator of sepsis-induced lung injury. Furthermore, because TNF challenge induced both sustained pulmonary and cardiac injury, TNF may be a common pathway for the multiple organ dysfunction that occurs during septic shock.
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PMID:TNF but not IL-1 in dogs causes lethal lung injury and multiple organ dysfunction similar to human sepsis. 176

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

This study was aimed at evaluating the effect of histamine on tumor necrosis factor (TNF alpha) secretion by purified human blood monocytes. TNF alpha was measured by radioimmunoassay. Histamine caused a dose-dependent inhibition of lipopolysaccharide-induced TNF alpha production from human blood monocytes, averaging maximally 50% at 10(-5) M. Preincubation of mononuclear cells with an H2 antagonist (cimetidine), but not with an H1 antagonist (promethazine) prevented this inhibitory effect of histamine. In conclusion, histamine causes, in vitro, a depression of TNF alpha secretion by human monocytes through activation of H2 receptors.
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PMID:Effect of histamine on tumor necrosis factor production by human monocytes. 193 30


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