Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:017444 (TNF)
 61,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In studying "hemorrhagic necrosis" of tumors produced by endotoxin, it was found that the serum of bacillus Calmette--Guerin (BCG)-infected mice treated with endotoxin contains a substance (tumor necrosis factor; TNF) which mimics the tumor necrotic action of endotoxin itself. TNF-positive serum is as effective as endotoxin itself in causing necrosis of the sarcoma Meth A and other transplanted tumors. A variety of tests indicate that TNF is not residual endotoxin, but a factor released from host cells, probably macrophages, by endotoxin. Corynebacteria and Zymosan, which like BCG induce hyperplasia of the reticulo-endothelial system, can substitute for BCG in priming mice for release of TNF by endotoxin. TNF is toxic in vitro for two neoplastic cell lines; it is not toxic for mouse embryo cultures. We propose that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.
Proc Natl Acad Sci U S A 1975 Sep
PMID:An endotoxin-induced serum factor that causes necrosis of tumors. 110 52

Thioglycollate-elicited macrophages (m phi), upon binding the lectin Griffonia simplicifolia IB4 (GSIB4) at the plasma membrane, are induced to secrete several low molecular weight proteins. In this investigation, results from specific ELISA and immunoprecipitation analysis of these molecules confirmed that the cytokine, tumor necrosis factor-alpha (TNF-alpha), belongs to the group of elicited proteins. This specific m phi response is directly influenced by the dose of GSIB4 used and the time in contact with the cells. At 40 micrograms/ml GSIB4, the maximum dose of lectin used, the m phi activity was equal to that achieved when the cells were incubated with an interferon-gamma/lipopolysaccharide (IFN/LPS) stimulus alone. Moreover, the data showed that TNF-mediated tumoricidal activity was significantly influenced by GSIB4 binding to the m phi membrane. When the lectin was incubated alone or in sequence with IFN/LPS, this ligand-receptor binding promoted the lysis of WEHI 164 tumor target cells. However, concurrent incubation of both IFN/LPS and GSIB4 with m phi significantly diminished the tumoricidal response. This suggested that one of the metabolic pathways utilized subsequent to receptor-ligand binding was altered by these interactions. When cyclic AMP (cAMP) and inositol triphosphate (IP3) levels were examined, the results showed that the concentration of cAMP was unchanged despite the fact that IP3 levels were significantly enhanced upon m phi-GSIB4 binding. Collectively, the data show that GSIB4 binding to specific glycoproteins in the m phi membrane induces TNF-alpha production and facilitates TNF-alpha dependent tumoricidal responses. It also appears that the transduction of the signal, in part, at least utilizes the phosphatidyl inositol pathway. Finally, it is noteworthy that m phi activity is influenced by the sequence in which GSIB4 is presented to the m phi relative to the IFN/LPS treatment.
J Cell Physiol 1992 Sep
PMID:Macrophage membrane glycoprotein binding of Griffonia simplicifolia I-B4 induces TNF-alpha production and a tumoricidal response. 132 45

Serum levels of the soluble form of tumour necrosis factor receptor type II (p75) (sTNF-R) were determined in HIV-infected individuals and risk groups and were then correlated with the course of infection and prognosis. sTNF-R levels were determined by an ELISA with MoAbs and polyclonal antibodies to urine-derived sTNF-R proteins. The mean +/- s.e. levels of sTNF-R in the sera of 49 HIV+ male homosexuals, 34 HIV- male homosexuals and 44 matched controls were 6.1 +/- 0.3 ng/ml, 4.4 +/- 0.3 ng/ml and 3.4 +/- 0.2 ng/ml, respectively. All these values were significantly different between each of the groups (P less than 0.001-0.05). Sequential studies of sTNF-R revealed higher levels following seroconversion in 5/8 individuals, remained persistently high during the asymptomatic phase of the infection and became even more elevated in some ARC and AIDS patients. At the same time TNF-alpha was undetectable in sera obtained from HIV+ male homosexuals and from healthy controls. This was independent of stage of HIV infection, serum sTNF-R level and type of ELISA kit used. These findings suggest that TNF-alpha/TNF-R system is turned on before and during HIV infection and raise the possibility that sTNF-R, the natural inhibitor of TNF, may be of importance in determining the course and probably prognosis of the disease.
Clin Exp Immunol 1992 Sep
PMID:Elevated serum levels of soluble tumour necrosis factor receptors (sTNF-R) in patients with HIV infection. 132 3

SV40 transformation of rodent fibroblasts generally produces cells that are highly sensitive to killing by activated macrophages. The cell line SV-COL-E8 (E8) is typical of SV40-transformed mouse fibroblasts in that it is readily lysed when exposed to activated macrophages. This killing is not due solely to TNF, because soluble TNF alone is incapable of lysing these cells. TNF is, however, necessary for lysis since antibodies to TNF will prevent macrophage-mediated lysis. Similarly, E8 is not sensitive to nitric oxide (NO); however, NO is also necessary for lysis since inhibition of NO generation (by coincubation with the arginine analogue NG-monomethyl-1-arginine) with Fe(II)) blocks lysis of E8 by activated macrophages. Cytolysis by macrophages is contact dependent, suggesting that the cell-associated TNF precursor may be involved in mediating cytolysis. However, transfected cell lines bearing cell-associated TNF precursor do not mediate killing of E8. Thus, killing of E8 either involves both TNF and NO in addition to a third, as yet unidentified, lytic mechanism, or killing requires the contact-dependent delivery of TNF and NO from the macrophage to its target.
J Immunol 1992 Sep 15
PMID:Both tumor necrosis factor and nitric oxide participate in lysis of simian virus 40-transformed cells by activated macrophages. 132 25

TNF-alpha (Cachectin) is a cytokine (tissue hormone) synthesized and secreted as a trimeric polypeptide; major producers are the cells of the RES after stimulation, e.g. by endotoxin. Its synthesis is strictly regulated. TNF elicits a great number of cell-specific responses. IL-1 and probably additional mediators cooperate in these effects. TNF is instrumental not only in the pathogenesis of inflammation, infections and some cell injuries, but also in the unspecific immune response, tumor toxicity and tissue homeostasis. TNF binding to specific receptors on cell surfaces initiates of secondary intracellular signals that, in turn, mediate the metabolic responses of the target cells. Pharmacological intervention may be envisaged at the level of synthesis (glucocorticoids, anti-oxidants) or interaction of the cytokine with its receptors.
Schweiz Rundsch Med Prax 1992 Sep 01
PMID:[Tumor necrosis factor alpha]. 132 75

Endotoxin shock is not only the reflexion of Gram-negative focal infection but also the consequence of dysfunction of the intestinal mucous barrier and a decline of the detoxication capacity, in particular of the hepatic mesenchymal phagocytic system during a critical state. Cytokines and the primary LPS complex and its lipid A resp. are of basic importance. They start the release of a large amount of TNF alpha, IL-1, IL-6, IL-8 and other cascades. Acute shock is controlled nowadays more frequently than in the past, however, there is a high risk of a very adverse reaction of remote organs, which is very adverse from the prognostic aspect. A series of laboratory markers has a greater validity than the clinical picture alone. For screening derived markers are used not primary markers. Despite this they provide adequate information. Prophylaxis and treatment include selective bacterial decontamination, or active or passive immunization (PSAEVA, hyperimmune sera), minidoses of dopamine in a continuous infusion, early enteral nutritional intervention, in particular enteral nutrition containing glutamine. Monoclonal and polyclonal antibodies against the LPS complex and cytokines are tested, blocking their receptors or possibly early plasmapheresis. Permanent pillars of therapeutic tactics are still a radical and early elimination of possible infectious foci and targeted administration of antibiotics and maintenance of the perfusion pressure and adequate oxygenation.
Cesk Epidemiol Mikrobiol Imunol 1992 Sep
PMID:[New findings in emergency care and resuscitation in patients at risk for endotoxic shock]. 133

Mice were thymectomized and depleted of CD4+ lymphocytes by treatment with monoclonal antibody to induce Pneumocystis carinii (PC) pneumonia (PCP). These mice were then exposed to aerosols of heat-treated Escherichia coli three times a week. Aerosol treatment for 10 d caused a slight reduction in numbers of PC nuclei in the lungs of mice, and treatment for 22 d resulted in nearly complete resolution of PCP. Large numbers of macrophages, polymorphonuclear leukocytes, and lymphocytes accumulated in lungs of aerosol-treated mice. Depletion of either CD8+ lymphocytes or asialo GM1+ cells that remained in the mice after CD4+ cell depletion had no effect on the ability of the mice to resolve PCP after E. coli aerosol treatments. However, depletion of Thy-1+ lymphocytes in these mice abrogated their ability to resolve PCP and reduced the numbers of macrophages that accumulated in the lungs. In addition, it was found that resolution of PCP induced by heat-treated E. coli aerosol treatments was also abrogated when mice were treated with polyclonal antibodies against tumor necrosis factor alpha (TNF-alpha). Thus, resolution of PCP in CD4+ lymphocyte-depleted mice by heat-treated E. coli aerosols was not dependent on either CD8+ or asialo GM1+ cells but was dependent on Thy-1+CD4-CD8- lymphocytes and on the participation of TNF. These results indicate that heat-treated E. coli aerosols can act as an immune response modifier by inducing resolution of PCP in mice by a mechanism not dependent on the presence of CD4+ lymphocytes.
J Exp Med 1992 Sep 01
PMID:Resolution of Pneumocystis carinii pneumonia in CD4+ lymphocyte-depleted mice given aerosols of heat-treated Escherichia coli. 135 3

We have previously established that eosinophils studied ex vivo from the sputum of asthmatics express intercellular adhesion molecule-1 (ICAM-1) and HLA-DR, whereas peripheral blood eosinophils do not express these surface proteins. On incubation of highly purified (greater than 99.5% pure) blood eosinophils from normal subjects with T cell supernatants, eosinophil ICAM-1 was induced in 24 h, whereas HLA-DR was maximally induced within 48 h. Recombinant cytokines that enable eosinophil survival (IL-5, IL-3, and granulocyte macrophage-CSF) were found to be unable to induce ICAM-1 or HLA-DR, even when pooled at concentrations individually required for eosinophil survival. However, synergy between these eosinophil survival factors and TNF (-alpha and -beta) was found mainly responsible for ICAM-1 induction, whereas synergy between IL-3 and IFN-gamma occurred for HLA-DR induction. Culture of eosinophils in the presence of cytokines and cycloheximide prevented expression of ICAM-1 and HLA-DR, showing that de novo eosinophil protein synthesis is occurring. At a functional level we demonstrate that ICAM-1-bearing eosinophils have increased adhesion capacity for autologous T cells. In contrast, HLA-DR-expressing eosinophils mediated Ag-specific proliferation of an autologous HLA-DR-restricted T cell clone that was inhibitable by anti-HLA-DR and anti-ICAM-1 mAb. Since eosinophil-mediated Ag presentation was inhibitable by treatment of eosinophils with glutaraldehyde or chloroquine, this suggests that eosinophils participate in Ag uptake, processing, and presentation and have accessory functions. Thus, through the induction of ICAM-1 and HLA-DR on tissue eosinophils, eosinophils have the capacity to interact with leukocytes and present Ag to T cells.
J Immunol 1992 Sep 15
PMID:Induction and function of eosinophil intercellular adhesion molecule-1 and HLA-DR. 135 3

Although glucocorticoids are a conventional treatment for lupus nephritis, the cellular and molecular mechanisms responsible for preventing renal injury are unknown. MRL-lpr mice develop an aggressive autoimmune nephritis. As these mice become nephritic, there is an increase in the renal expression of molecules that permit or facilitate immune interactions, including MHC class II (Ia) antigens, intercellular adhesion molecule-1 (ICAM-1), and pro-inflammatory cytokines. Because dexamethasone (Dex) alters Ia antigen expression and suppresses cytokine generation, the authors prophylactically treated MRL-lpr mice and investigated the relative importance of these molecules in inducing renal injury. MRL-lpr mice given Dex (0.4 mg/kg/d) from age 6 weeks were killed 4, 8, and 16 weeks after the initiation of therapy, and tissue was removed for histology and extraction of total RNA. Dex prevented lymphadenopathy and renal injury. DEX eliminated the marked Thy 1.2+ lymphocytic infiltrates within the kidney and preserved normal renal histology and urinary protein levels. Northern blot analysis of steady-state mRNA transcripts indicated Dex suppressed a four-fold increase in kidney major histo-compatibility complex class II (Ia) molecule antigen mRNA seen by age 22 weeks (Ia/beta-actin ratios = 0.64 +/- 0.50 versus 2.32 +/- 0.48, P less than 0.01), but did not alter the costimulatory molecules ICAM-1 or tumor necrosis factor alpha (TNF alpha). Although all of these molecules are important mediators of inflammation, autoimmune nephritis was ameliorated without alteration of TNF alpha gene transcription or ICAM-1 transcription and surface expression. This study suggests that the benefit of steroids in nephritis stems from preventing lymphocyte infiltration into the kidney and decreasing immune interactions by limiting Ia expression.
Am J Pathol 1992 Sep
PMID:Dexamethasone prevents autoimmune nephritis and reduces renal expression of Ia but not costimulatory signals. 135 33

Although tumor necrosis factor alpha (TNF alpha) exerts a variety of activities on hematopoietic cells, suggesting it may have some potential therapeutic applications, its long-term effects on hematopoiesis are not well defined. Therefore, we took the advantage of long-term bone marrow cultures (LTBMCs) to evaluate the long-term role of TNF alpha on both the microenvironment and the hematopoietic progenitors. LTBMCs were inoculated with 100 U/ml of recombinant human TNF alpha (rhTNF alpha) either at the onset of the cultures (d0) or at day 21 (d21) when the adherent layer (AL) was already established. Then TNF alpha was added at each weekly medium change. The cellularity and the content of progenitors in both the nonadherent layer (NAL) and AL, the formation of the AL, and the presence of various cytokines in the supernatants were examined weekly. The data showed 1) a strong and durable inhibitory effect on total nonadherent cells; 2) a rapid and transient inhibition of NA progenitors, whereas adherent progenitors were lately affected; and 3) microenvironmental changes consisting of the disappearance of adipocytes and the secretion of high levels of interleukin 6. The results suggest that the inhibitory effects of TNF alpha on the NAL are in part counterbalanced by stromal modifications that in turn lead to a faster exhaustion of hematopoiesis.
Exp Hematol 1992 Sep
PMID:Tumor necrosis factor alpha in human long-term bone marrow cultures: distinct effects on nonadherent and adherent progenitors. 138 Apr 63


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