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)

Incubation of Swiss 3T3 or L929 cells with tumor necrosis factor (TNF) leads to the rapid stimulation of several cytosolic Ser/Thr kinases active toward myelin basic protein, the S6 peptide (RRLSSLR), the G peptide (SPQPSRRGSESSEE), and Kemptide (LRRASLG). This confirms the hypothesis that kinases other than protein kinases A and C may be involved in the TNF signal transduction. Chromatography on Mono Q resolved multiple kinase peaks with each substrate tested and moreover revealed a TNF-mediated casein kinase-2 activation in both cell lines, measurable with the specific RRREEESEEE peptide or with the G peptide. The TNF-stimulated myelin basic protein kinases-1 and -2 were identified as extracellular signal-regulated kinases-2 and -1, respectively, based on their elution pattern on Mono Q chromatography, their inactivation by protein phosphatase action, their reaction with phosphothreonine and phosphotyrosine antibodies, and by their migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as 42- and 44-kDa proteins recognized by anti-extracellular signal-regulated kinase antibodies.
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PMID:Tumor necrosis factor stimulates multiple serine/threonine protein kinases in Swiss 3T3 and L929 cells. Implication of casein kinase-2 and extracellular signal-regulated kinases in the tumor necrosis factor signal transduction pathway. 128 78

Agents that can arrest cellular proliferation are now providing insights into mechanisms of growth factor action and how this action may be controlled. It is shown here that the macrophage activating agents tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma), and lipopolysaccharide (LPS) can maximally inhibit colony stimulating factor-1 (CSF-1)-induced, murine bone marrow-derived macrophage (BMM) DNA synthesis even when added 8-12 h after the growth factor, a period coinciding with the G1/S-phase border of the BMM cell cycle. This inhibition was independent of autocrine PGE2 production or increased cAMP levels. In order to compare the mode of action of these agents, their effects on a number of other BMM responses in the absence or presence of CSF-1 were examined. All three agents stimulated BMM protein synthesis; TNF alpha and LPS, but not IFN gamma, stimulated BMM Na+/H+ exchange and Na+,K(+)-ATPase activities, as well as c-fos mRNA levels. IFN gamma did not inhibit the CSF-1-induced Na+,K(+)-ATPase activity. TNF alpha and LPS inhibited both CSF-1-stimulated urokinase-type plasminogen activator (u-PA) mRNA levels and u-PA activity in BMM, whereas IFN gamma lowered only the u-PA activity. In contrast, LPS and IFN gamma, but not TNF alpha, inhibited CSF-1-induced BMM c-myc mRNA levels, the lack of effect of TNF alpha dissociating the inhibition of DNA synthesis and decreased c-myc mRNA expression for this cytokine. These results indicate that certain biochemical responses are common to both growth factors and inhibitors of BMM DNA synthesis and that TNF alpha, IFN gamma, and LPS, even though they all have a common action in suppressing DNA synthesis, activate multiple signaling pathways in BMM, only some of which overlap or converge.
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PMID:Biochemical events accompanying macrophage activation and the inhibition of colony-stimulating factor-1-induced macrophage proliferation by tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. 133 37

The APO-1 antigen as defined by the mouse monoclonal antibody anti-APO-1 was previously found to be expressed on the cell surface of activated human T and B lymphocytes and a variety of malignant human lymphoid cell lines. Cross-linking of the APO-1 antigen by anti-APO-1 induced programmed cell death, apoptosis, of APO-1 positive cells. To characterize the APO-1 cell surface molecule and to better understand its role in induction of apoptosis, the APO-1 protein was purified to homogeneity from membranes of SKW6.4 B lymphoblastoid cells by solubilization with sodium deoxycholate, affinity chromatography with anti-APO-1 antibody, and reversed phase high performance liquid chromatography. Each purification step was followed by an APO-1-specific solid phase enzyme-linked immunosorbent assay using the monoclonal antibody anti-APO-1. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the APO-1 antigen was found to be a membrane glycoprotein of 48-kDa. Endoproteinase-cleaved peptides of the APO-1 protein were subjected to amino acid sequencing, and corresponding oligonucleotides were used to identify a full-length APO-1 cDNA clone from an SKW6.4 cDNA library. The deduced amino acid sequence of APO-1 showed sequence identity with the Fas antigen, a cysteine-rich transmembrane protein of 335 amino acids with significant similarity to the members of the tumor necrosis factor/nerve growth factor receptor superfamily. The APO-1 antigen was expressed upon transfection of APO-1 cDNA into BL60-P7 Burkitt's lymphoma cells and conferred sensitivity towards anti-APO-1-induced apoptosis to the transfectants.
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PMID:Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. 137 28

Acidic fibroblast growth factor (aFGF) enhances nerve growth factor (NGF) synthesis by astrocytes obtained from various brain regions. NGF secretion by fibrous-shaped astrocytes transformed by dibutyryl-cAMP (db-cAMP) pretreatment was less than that by untreated astrocytes. However, aFGF also enhanced NGF secretion by fibrous-shaped astrocytes. The effects of various kinds of intracellular signaling modulators on NGF synthesis were examined. None of the following second messenger effectors had an effect on NGF synthesis: protein kinase C (PKC) agonist (phorbol myristate acetate (PMA)) or antagonist (sphingosine (SP)). LiCl, and ionomycin (Iono). Further, increases of intracellular cAMP by forskolin (FK) or db-cAMP have no significant effect on NGF synthesis in astrocytes under a standard culture condition. However, NGF synthesis by astrocytes in the presence of aFGF was significantly enhanced by db-cAMP, but not by FK or sodium butyrate. These results indicate that an excessive amount of cAMP enhances the effect of aFGF on NGF synthesis in astrocytes. NGF synthesis in astrocytes was not affected by treatment with anti-aFGF or anti-bFGF neutralizing antibodies, indicating that FGFs are not involved in the autocrine regulation of NGF synthesis in astrocytes. Transforming growth factor-beta 1 (TGF-beta 1), which inhibits some effects of FGFs, increased NGF synthesis in concert with aFGF. Furthermore, the highest NGF synthesis was observed when astrocytes were stimulated by all of the following cytokines: aFGF, interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and TGF-beta 1. The mechanism regulating NGF synthesis in fibroblasts obtained from prenatal rat skin was also investigated. Acidic FGF, basic FGF (bFGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-alpha (TGF-alpha), TGF-beta 1, IL-1 beta, and TNF-alpha were found to be regulators of NGF synthesis in skin fibroblasts. Among these cytokines, aFGF is the most potent regulator of NGF synthesis in fibroblasts. NGF synthesis by skin fibroblasts, either in the presence or absence of aFGF, was not modified by any of the following: FK, PMA, SP, LiCl, and Iono. However, db-cAMP significantly enhanced NGF synthesis in both conditions. Sodium butyrate enhanced NGF synthesis in the presence of aFGF, but not in the absence of aFGF. These results suggest that an excessive amount of cAMP and butyrate moiety regulate NGF synthesis in skin fibroblasts in different ways.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cooperative regulation of nerve growth factor synthesis and secretion in fibroblasts and astrocytes by fibroblast growth factor and other cytokines. 137 78

Nitric oxide (NO) functions as an intercellular messenger molecule in such varied contexts as neurotransmission, immune regulation, and the control of vascular tone. We report that NO, delivered as purified gas or released from the pharmacologic NO donors sodium nitroprusside or 6-morpholino-sydnonimine, caused monocytic differentiation of cells of the human myeloid leukemia cell line HL-60 and altered gene expression. The treated cells stopped proliferating, became spread and vacuolated, had increased expression of nonspecific esterase and the monocyte marker CD14, and displayed increased capacity to produce hydrogen peroxide. Furthermore, these treated cells had increased steady-state expression of messenger RNA (mRNA) for tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), but decreased expression of mRNA for the proto-oncogenes c-myc and c-myb. The increase in TNF-alpha and IL-1 beta mRNA levels was due (at least in part) to a new transcription of these specific mRNAs. NO elaborated in the bone marrow microenvironment may have a role in normal and malignant hematopoietic cell growth and differentiation.
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PMID:Nitric oxide modulation of human leukemia cell differentiation and gene expression. 138 8

In this report we show that the adenovirus E3 region 14.7 kDa protein, heat and sodium arsenite, which have been defined previously as inhibitors of cytolysis, inhibit the tumor necrosis factor-alpha (TNF)-induced release of 3H-arachidonic acid from cycloheximide-sensitized C3HA fibroblasts. Since the A23187-induced release of 3H-a.a. was unaffected, our results suggest that these inhibitors provide resistance to lysis by selectively interfering with the lytic response pathway. Our results also show that heat and sodium arsenite can themselves induce the release of 3H-arachidonic acid. These results raise the possibility that stressor-induced resistance to TNF results from the selective desensitization of phospholipase A2.
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PMID:The adenovirus E3 region 14.7 kDa protein, heat and sodium arsenite inhibit the TNF-induced release of arachidonic acid. 141 42

Interleukin-1 (IL-1) is an important mediator in inflammation and immunological processes. The findings of native IL-1 inhibitors suggest a negative feedback mechanism to down-regulate IL-1 mediated acute inflammation. IL-1 inhibitors were also found elevated in disease states associated with high IL-1 levels. We have previously described one such IL-1 inhibitor derived from the human M20 myelomonocytic cell line. In this paper we present several biological and biochemical characteristics of the M20 IL-1 inhibitor. Various in vitro activities of the inhibitor are described and its IL-1 specificity in these assays is demonstrated. Purification of the inhibitor was performed by DEAE-high performance liquid chromatography, isoelectric focusing, gel filtration and dye ligand chromatography column. This protein factor has a MW of 52 +/- 4 kDa and a pI of 4.15 +/- 0.1. The inhibitor has no cross-reactivity against a panel of known cytokines (IL-1 alpha, IL-1 beta, IL-2, sIL-2R, IL-6, tumor necrosis factor (TNF), interferon-gamma (IFN-gamma)) and is distinct from the IL-1 receptor antagonist (IL-1ra). The purified IL-1 inhibitor was destroyed by trypsin, 2-mercaptoethanol, sodium dodecyl sulfate and extremes in pH and in temperature. Only IL-1 induced (but not the IL-2, IL-6 or TNF induced) thymocyte proliferation and PGE2 production by fibroblasts were inhibited by the inhibitor, thus showing specificity to IL-1 in these assays.
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PMID:The M20 IL-1 inhibitor. II. Biological characterization. 143 Nov 47

Toxins may be specifically directed to tumor cells and the toxins' potency greatly increased by covalent conjugation to monoclonal antibodies recognizing tumor-associated antigens. Antibody 15A8, an immunoglobulin G1 (IgG1) subclass anti-human breast carcinoma murine monoclonal antibody and gelonin, a plant toxin, were covalently modified with N-succimindyl 3-(2-pyridyldithio) proprionate and iminothiolane, respectively, and allowed to cross-link. 15A8-gelonin conjugates were purified from unreacted antibody and free gelonin by gel filtration and blue sepharose chromatography. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the final product contained two bands corresponding to antibody:gelonin conjugates of 1:1 (predominant) and 1:2. There were no contaminating amounts of free antibody or free toxin in the preparation. The yield of the final purified 15A8-gelonin conjugate was approximately 20% based on the amount of starting antibody. The protein synthesis inhibitory activity of the immunoconjugate was assessed by in vitro rabbit reticulocyte translation assay. This functional activity was normalized to that of unmodified gelonin for use in in vitro antiproliferative assays against antigen-negative (Hs294t human melanoma) and antigen-positive (ME-180 human cervical carcinoma) cell lines. Antigen-negative Hs294t cells incubated for 72 hours with 15A8-gelonin immunotoxin showed no increased cytotoxicity compared with HS294t cells exposed to free gelonin alone. However, the immunotoxin was preferentially toxic to antigen-positive ME-180 cells; over 5 logs greater cell kill was observed after 72 hours exposure to 15A8-gelonin than after the same exposure to gelonin alone. Various lysosomotropic agents augmented 15A8-gelonin cytotoxicity; the most effective potentiating agent appeared to be monensin. In addition, the chemotherapeutic agents L-phenylalanine mustard (L-PAM), 5-fluorouracil, vincristine, and bleomycin, and the biological response modifiers interferon-alpha and tumor necrosis factor-alpha were shown to augment 15A8-gelonin cytotoxicity. Should in vivo pharmacology and therapeutic studies confirm these in vitro findings, 15A8-gelonin conjugate may be a potent agent for therapy of cancer in man.
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PMID:A gelonin-containing immunotoxin directed against human breast carcinoma. 144 65

The aim of this study was to establish a cytokine-free, serum-free system which would enable the long-term survival and proliferation of human peripheral blood monocytes. Monocytes were isolated from peripheral blood mononuclear cells (PBMC) by adherence to untreated plastic petri dishes and maintained up to 6 weeks in serum-free medium (SFM) consisting of IMEM, insulin, transferrin, sodium selenite and BSA. Maximal cell proliferation occurred during the first 2 weeks of culture and corresponded to the appearance of large numbers of pure, nonadherent culture-derived macrophages. Monocyte maturation was characterised by the modulation of specific cell surface antigens. The percentage of cells staining for the transferrin receptor increased with time, whereas the percentages of cells expressing CD11b, CD11c and HLA-DR remained greater than 60% for the 15 days studied. The mean fluorescent intensities (MFI) of all these antibodies increased significantly with time. The only differences found between the adherent and nonadherent cells, using the above antibodies, were with the MFI for CD11b and CD11c. In both cases, the intensity of staining was significantly greater in the adherent cells. Estimation of cytokine production by cells maintained for 5 weeks in SFM found that they constitutively produced large amounts of macrophage colony-stimulating factor (M-CSF) in the absence of any exogenous stimuli. These cells were also found to secrete high levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) during the 1st week and granulocyte macrophage colony-stimulating factor (GM-CSF) during the 3rd week. However, the addition of exogenous GM-CSF (5 U/ml, S5) was found to significantly inhibit monocyte proliferation up to 17 days. This is the first report of proliferation associated with long-term survival of culture derived macrophages in a serum-free, cytokine-free system.
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PMID:Monocyte proliferation in a cytokine-free, serum-free system. 151 90

Macrophage hyperactivity with increased production of tumor necrosis factor, interleukin 6, interleukin 1, and prostaglandins has been demonstrated in the injured patient, but the effect of this on the clinical outcome is unclear. We studied the effect of combination interleukin 1 beta and indomethacin sodium therapy on macrophage hyperactivity and survival after sepsis in a murine burn model. Macrophage interleukin 1, interleukin 6, and tumor necrosis factor alpha production were all significantly increased 10 days after thermal injury. Treatment with recombinant human interleukin 1 beta in combination with indomethacin significantly reduced this overproduction of cytokines to normal levels, and this was associated with an improvement in survival after septic challenge (52% survival in interleukin 1 beta-indomethacin-treated group compared with 22% in burned vehicle control mice). Burned mice that received either interleukin 1 beta or indomethacin alone demonstrated tumor necrosis factor and interleukin 6 production and survival intermediate between the interleukin 1 beta-indomethacin-treated group and the vehicle control group. Control of macrophage hyperactivity is associated with improved survival from subsequent sepsis and offers a potential new strategy for the treatment of immune dysfunction in thermally injured patients.
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PMID:Modulation of macrophage hyperactivity improves survival in a burn-sepsis model. 154 91


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