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Query: UNIPROT:P06889 (Mol)
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Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine produced principally by mononuclear cells, is released in response to a variety of pulmonary pathogens. We hypothesized that release of TNF in the lung is a normal part of the host response to intratracheal challenge with Pneumocystis carinii. To test this hypothesis, we measured TNF in bronchoalveolar lavage fluid (BALF) in normal and CD4-depleted mice at various intervals in acute and chronically infected animals. To assess the cell of origin and the control of TNF release in the lung, we measured mRNA for TNF by a competitive polymerase chain reaction and assessed the capacity of adherence-enriched cells to produce TNF in vitro in response to lipopolysaccharide. Our data demonstrate that TNF peaks at 3 h in both control and CD4-depleted mice after acute challenge with P. carinii and this increase in TNF precedes the influx of inflammatory cells into the lung. TNF levels in BALF return to undetectable levels by day 3. In chronically infected animals, there is a 5-fold increase in mRNA for TNF in adherent cells which is associated with an increased capacity to release TNF in vitro. These data suggest that TNF is a normal host response to P. carinii infection; however, there is no difference in acute TNF release between control animals that clear their infection and CD4-depleted animals that develop chronic infection. TNF is upregulated in chronically infected animals, but CD4 depletion results in the loss of additional host factors essential for resolution of this infection.
Am J Respir Cell Mol Biol 1993 Apr
PMID:Alveolar macrophage release of tumor necrosis factor during murine Pneumocystis carinii pneumonia. 847 31

Accumulation and adhesion of leukocytes to cardiac myocytes play important roles in the pathogenesis of inflammation-mediated myocardial injury such as ischaemia/reperfusion and myocarditis. The involvement of leukocyte chemotactic factors has been speculated in these processes. We investigated the expression of cytokine-induced neutrophil chemoattractant (CINC) in rat cardiac myocytes. CINC is a rat equivalent of human interleukin-8. On exposure to interleukin-1 alpha (IL-1 alpha), cultured neonatal rat cardiac myocytes released appreciable levels of CINC both dose- and time-dependently. Tumor necrosis factor-alpha and lipopolysaccharide also significantly increased CINC accumulation in the culture supernatant. CINC mRNA expression was not observed in unstimulated myocytes, however, the expression was markedly induced by exposure to IL-1 alpha with a peak elevation at 3 h. Potent chemotactic activity for neutrophils was detected in the supernatant of cultured rat cardiac myocytes by stimulation with IL-1 alpha. This IL-1 alpha-induced chemotactic activity was significantly inhibited by polyclonal anti-CINC antiserum. Addition of dexamethasone, genistein, actinomycin D or cycloheximide significantly suppressed the IL-1 alpha-induced CINC accumulation. Under hypoxia (95%N2 + 5%CO2), CINC accumulation was increased in a time-dependent manner, and reoxygenation after hypoxia further intensified CINC accumulation. This hypoxia reoxygenation-induced CINC expression was significantly inhibited by pretreatment with dexamethasone. In conclusion, inflammatory stimuli induce the expression of CINC in rat cardiac myocytes, which may lead to myocardial injury via accumulation and activation of neutrophils.
J Mol Cell Cardiol 1995 Sep
PMID:Expression of cytokine-induced neutrophil chemoattractant in rat cardiac myocytes. 852 63

Tumor necrosis factor (TNF) is an inflammatory cytokine produced by many cell types which may contribute to the pathophysiology of a variety of lung diseases. In this study we have used Ro 45-2081 (a soluble receptor composed of the human p55 TNF receptor and human heavy-chain immunoglobulin G) to explore the role of TNF in the acute inflammatory response in the rat lung to intravenous injection of Sephadex beads. The effects of Ro 45-2081 have also been compared with those of dexamethasone. At 24 and 72 h after Sephadex, there was a significant increase in the total number of leukocytes in bronchoalveolar lavage fluid (BALF). At 24 h, the number of neutrophils comprised around 50% of the total leukocyte number, decreasing to around 10% of total by 72 h. The eosinophil count was maintained at around 10% of the total leukocyte number. Pretreatment with either Ro 45-2081 [1 and 3 mg kg-1, intraperitoneally (i.p.)] or dexamethasone (0.1 and 0.3 mg kg-1, i.p.) inhibited the neutrophilia at 24 h after Sephadex, although Ro 45-2081 had no significant effect on total cell number. At 72 h after Sephadex, Ro 45-2081 (1 and 3 mg kg-1, i.p., daily) significantly reduced the neutrophil influx into BALF but had no inhibitory effect on eosinophil number. In contrast, dexamethasone (0.1 and 0.3 mg kg-1, i.p., daily) virtually abolished the infiltration of neutrophils and eosinophils into BALF. The lack of effect of Ro 45-2081 on eosinophil infiltration into the rat lung and the inhibition caused by dexamethasone suggest that factors other than TNF are involved in this part of the inflammatory response induced by Sephadex. However, the inhibitory effects of Ro 45-2081 show that TNF may play an important role in the recruitment of neutrophils into the lungs of Sephadex-treated rats.
Am J Respir Cell Mol Biol 1996 May
PMID:Inhibition of Sephadex-induced lung injury in the rat by Ro 45-2081, a tumor necrosis factor receptor fusion protein. 862 50

Tumor necrosis factor (TNF) mediates a wide variety of disease states including septic shock, acute and chronic inflammation, and cachexia. Recently, a multivalent guanylhydrazone (CNI-1493) developed as an inhibitor of macrophage activation was shown to suppress TNF production and protect against tissue inflammation and endotoxin lethality [Bianchi, M., Ulrich, P., Bloom, O., Meistrell, M., Zimmerman, G. A., Schmidtmayerova, H., Bukrinsky, M., Donnelley, T., Bucala, R., Sherry, B., Manogue, K. R., Tortolani, A. J., Cerami, A. & Tracey, K. J. (1995) Mol. Med. 1, 254-266, and Bianchi, M., Bloom, O., Raabe, T., Cohen, P. S., Chesney, J., Sherry, B., Schmidtmayerova, H., Zhang, X., Bukrinsky, M., Ulrich, P., Cerami, A. & Tracey, J. (1996) J. Exp. Med., in press]. We have now elucidated the mechanism by which CNI-1493 inhibits macrophage TNF synthesis and show here that it acts through suppression of TNF translation efficiency. CNI-1493 blocked neither the lipopolysaccharide (LPS)-induced increases in the expression of TNF mRNA nor the translocation of nuclear factor NF-kappa B to the nucleus in macrophages activated by 15 min of LPS stimulation, indicating that CNI-1493 does not interfere with early NF-kappa B-mediated transcriptional regulation of TNF. However, synthesis of the 26-kDa membrane form of TNF was effectively blocked by CNI-1493. Further evidence for the translational suppression of TNF is given by experiments using chloram-phenicol acetyltransferase (CAT) constructs containing elements of the TNF gene that are involved in TNF translational regulation. Both the 5' and 3' untranslated regions of the TNF gene were required to elicit maximal translational suppression by CNI-1493. Identification of the molecular target through which CNI-1493 inhibits TNF translation should provide insight into the regulation of macrophage activation and mechanisms of inflammation.
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PMID:CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. 863 99

Tumor necrosis factor-alpha (TNF) is associated with developmental and injury-related events in the central nervous system (CNS). In the present study, we have examined the role of TNF on neurons using the clonal murine neuroblastoma line, N1E-115 (N1E). N1E cells represent a well-defined model for studying neuronal development since they can be maintained as either undifferentiated, mitotically active neuroblasts or as differentiated, mature neurons. Northern and reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that both undifferentiated and differentiated N1Es express transcripts for the 55 kDa TNF receptor (TNFR), but not the 75 kDa TNFR. The biological activity of the expressed TNF receptor was demonstrated by a dose dependent cytotoxicity to either recombinant murine or human TNF when the cells were incubated with the transcriptional inhibitor actinomycin D. The lack of the 75 kDa receptor mRNA expression and the dose dependent response to rHuTNF, an agonist specific for the murine 55 kDa receptor, suggest that the TNF induced cytotoxicity is mediated through the 55 kDa receptor in both the undifferentiated and differentiated N1Es. Light microscopic observations, flow cytometric analysis of hypodiploid DNA, and electrophoretic analysis of nucleosomal DNA fragmentation of N1Es treated with actinomycin D and TNF revealed features characteristic of both necrotic and apoptotic cell death. These findings demonstrate that blast and mature N1E cells express the 55 kDa TNF receptor which is responsible for inducing both necrotic and apoptotic death in these cells. The observation that actinomycin D renders N1E cells susceptible to the cytotoxic effects of TNF indicates that a sensitization step, such as removal of an endogenous protective factor or viral-mediated inhibition of transcription, may be necessary for TNF cytotoxicity in neurons.
Brain Res Mol Brain Res 1996 Jun
PMID:An endogenous 55 kDa TNF receptor mediates cell death in a neural cell line. 879 10

Macrophage colony-stimulating factor (M-CSF) is a protein which is necessary for proliferation and differentiation of monocyte-macrophage precursor cells. We examined the effect of M-CSF on the cytokine production using BCG sensitized mice in vivo. On Day 0, BCG 1 mg/mouse was injected via the tail vein. Starting from Day 2, M-CSF 30 mu g/mouse (1 X 10(8) U/mg) was injected every 2 days for a total of six times (Day 2, 4, 6, 8, 10 and 12). On Day 14. LPS 25 mu g/mouse was injected via the tail vein, and Interferon (IFN)/Tumor necrosis factor-alpha (TNF-alpha) in serum were determined. The productions of IFN and TNF-alpha were suppressed significantly. These cytokine production-suppressive effects of M-CSF were found also in the in vitro experimental system using spleen cells collected. On Day 14, spleen cells were collected and adjusted to 5 X 10(6) cells/ml. 20 micro-grams of LPS was added to 2ml of spleen cells and they were incubated in a C02 incubator for 24 hours. IFN and TNF-alpha in the supernatant were determined. In the experiment using nude mice, the cytokine suppressive effect of M-CSF was not observed. MLR test was performed with spleen cells of C57BL/6 treated with M-CSF as the responder cells, and spleen cells of C3H were treated with mitomycin C as the stimulator cells. MLR was suppressed significantly by administration of M-CSF. These results might possibly reflect the actual effect of M-CSF in the living body, and the T-cell and cellular immunity might be concerned with the mechanism of the cytokine production-suppressive effect of M-CSF.
Res Commun Mol Pathol Pharmacol 1996 Feb
PMID:Cytokine production-suppressive effect by macrophage colony-stimulating factor (M-CSF). 883 8

Tumor necrosis factor (TNF) may contribute to the pathogenesis of inflammatory airway disorders via the regulation of inflammatory and cellular immune responses. Shed cell surface TNF receptors can act as soluble TNF binding proteins and modulate TNF biological activity. We report that normal human airway epithelial cells, as well as two human airway epithelial cell lines, shed soluble type I TNF receptors (sTNF-RI) in a concentration-dependent fashion following protein kinase C (PKC) activation by PMA. Interleukin (IL)-1beta also induced concentration-dependent sTNF-RI shedding from NCI-H292 cells, which could be inhibited by the PKC inhibitor calphostin C. Since corticosteroids are commonly utilized as antiinflammatory agents in airway disorders, the effect of dexamethasone on sTNF-RI release was assessed. Dexamethasone inhibited constitutive, as well as PMA- and IL-1beta-mediated sTNF-RI release from NCI-H292 cells in a concentration-dependent fashion. Furthermore, dexamethasone increased while PMA decreased total cellular 55 kDa TNF-RI protein as detected by immunoblotting. These changes in total cellular 55kDa TNF-RI protein did not appear to be mediated at the mRNA level, as assessed by ribonuclease protection assays. This suggests that sTNF-RI shedding represents a mechanism by which airway epithelial cells can actively participate in local cytokine networks and modulate TNF-mediated inflammation. Furthermore, since corticosteroids inhibit sTNF-RI release and are known to downregulate TNF synthesis, this may represent a mechanism by which equilibrium between TNF ligand and soluble binding protein is maintained in the airway microenvironment.
Am J Respir Cell Mol Biol 1996 Mar
PMID:Protein kinase C, interleukin-1 beta, and corticosteroids regulate shedding of the type I, 55 kDa TNF receptor from human airway epithelial cells. 884 76

Tumor necrosis factor-alpha (TNF-alpha), a potent cytokine mainly secreted by macrophages exerts pleiotropic effects on different cell types. However, the intracellular mediators of its action are not yet well characterized. To get an insight into endogenous cytoprotective mechanisms, we developed an in vitro model based on cultured cardiomyocytes treated with TNF-alpha at which we examined gene expression of heat shock proteins (HSP-27, HSP-70 and ubiquitin). Cardiomyocytes were isolated from the hearts of 18 day old fetal mice by enzymatic dissociation and grown in minimum essential medium containing 10% fetal calf serum. Spontaneously contractile cells were serum deprived for 24 h and treated with TNF-alpha (25 ng/ml) for 1, 2, 4, 6, 8, 12, and 24 h After each incubation, cells were processed to extract total proteins for Western and total RNA for Northern blot analyses. TNF-alpha induced arrhythmias and cessation of spontaneous contractions in a concentration and time dependent manner. Steady state (ubiquitin) or undetectable mRNA levels (HSP-27, HSP-70) were drastically induced (> 4 fold for all three genes vs untreated control cells) by TNF-alpha, reaching maximal values between 6-8 h of stimulation. Thereafter, the expression of these stress genes declined but remained elevated as compared to control. By Western blot analysis, we found increased multiple bands of ubiquitin protein conjugates in TNF-alpha treated cells whereas no significant change in HSP-27 protein accumulation until 12 h was observed as compared to control. 24 h of TNF-alpha incubation resulted in partial cellular necrosis. Our results indicate that TNF-alpha induces in cardiomyocytes transiently gene expression for cytoprotective molecules like HSP-27, HSP-70 and ubiquitin, suggesting these stress proteins to participate in subsequent defense mechanisms, for example in postischemic myocardial recovery.
Mol Cell Biochem
PMID:Cytoprotective mechanisms in cultured cardiomyocytes. 890 76

The function of vascular endothelial cells is to adjust blood vessel tonus, which contributes to maintaining homeostasis within blood vessels. However, inflammatory cytokines are produced in response to invasion by stimulating vascular endothelial cells and sometimes lead to shock or multiple organ failure. In the present study, we assessed cytokines in sepsis and septic shock, and various factors that are said to have a damaging effect on vascular endothelium. Endotoxin was measured by endotoxin-specific methods. Tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and interleukin 8 (IL-8) were measured by enzyme-linked immunosorbent assay (ELISA). Endothelin-I was measured by radioimmunoassay (RIA). Nitric oxide was measured as metabolites of nitrite and nitrate oxides (NOx) by a method based on the Griess method. Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (PGF 1 alpha) were both measured by RIA. All of the factors except endotoxin were significantly higher in the septic shock group than in the non-shock group and significantly higher in the non-survivor group than in the survivor group. Significant correlations were also found between endothelin-1 and NOx and between TXB2 and PG1 alpha. Significant correlations were also found between TNF-alpha and IL-6, endothelin-1, NOx and TXB2, but no significant correlations were detected between any of them and endotoxin. In serious diseases such as septic shock, the vascular endothelial constricting factors, endothelin and TXB2, and the blood vessel relaxing factors NOx and PGF1 alpha increase almost simultaneously. This suggests that the body's regulating mechanisms are disrupted in these serious conditions. The results of this study also suggest that inflammatory cytokines may be involved in stimulating the production of these factors.
Res Commun Mol Pathol Pharmacol 1996 Oct
PMID:Functional modification of vascular endothelial cells by cytokines during septic shock. 894 12

High levels of nitric oxide (NO) have been reported in exhaled air of asthmatic individuals. Because alveolar macrophages (AM) are major producers of cytokines, and bronchoalveolar lavage fluid (BALF) from asthmatic individuals contains increased levels of inflammatory cytokines, this study was undertaken to determine whether NO modified the production of inflammatory cytokines by human AM. AM were obtained from normal volunteers by fiberoptic bronchoscopy. Tumor necrosis factor-alpha (TNF-alpha) production stimulated by lipopolysaccharide (LPS; 0.5 microg/ml) was measured with an enzyme-linked immunosorbent assay (ELISA). NO generated from 2,2-(hydroxynitrosohydrazono)-bis-ethanamine (DETA NONOate) (0.1 to 1.0 mM) inhibited TNF-alpha secretion in a dose-dependent manner. At 1 mM DETA NONOate, mean inhibition (+/- SEM) of TNF-alpha secretion was 56 +/- 4% (P = 0.002). To determine whether this effect was cytokine specific, interleukin-1beta (IL-1beta) and macrophage inflammatory protein-1alpha (MIP-1alpha) were evaluated, and DETA NONOate was also found to inhibit both of these cytokines. Basal cytokine levels from unstimulated AM were unaffected by NO. These findings indicate that NO is a potent inhibitor of cytokine production by stimulated human AM.
Am J Respir Cell Mol Biol 1997 Sep
PMID:Nitric oxide inhibits inflammatory cytokine production by human alveolar macrophages. 930 13


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