Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the current study, we describe cytokine and Escherichia coli lipopolysaccharide (LPS) induction of nitric oxide (NO) synthase mRNA levels in cultured smooth muscle from rat pulmonary artery (RPASM). Exposure of RPASM to interleukin-1 beta, interferon-gamma, or LPS alone did not significantly affect NO synthesis, as determined by nitrite concentrations in media. Exposure to tumor necrosis factor-alpha caused a modest (2x) increase in nitrite production. In contrast, exposure to a combination of the above three cytokines and LPS caused a large increase in NO synthesis. Exposure of RPASM to this combination caused an increase in mRNA levels of NO synthase (as described by Northern blot analysis with 32P-cDNA probe to an inducible form of NO synthase present in murine macrophages) that was apparent as early as 4 h. Expression of the induced gene product after exposure to the cytokine and LPS mixture was evident by significant increases in nitrite production at 12 h. Production of nitrite was completely abolished in the presence of NG-monomethyl-L-arginine (NMA), and this inhibition was reversible by the addition of excess L-arginine. NO synthase mRNA levels were not affected by NMA. The nitrite production induced by the combination of cytokines and LPS was abolished by pretreating cells with cycloheximide. These data indicate that a combination of cytokines and LPS affect expression of the gene for the inducible form of NO synthase in cultured RPASM.
Am J Respir Cell Mol Biol 1992 Nov
PMID:Cytokines and lipopolysaccharide induce nitric oxide synthase in cultured rat pulmonary artery smooth muscle. 138 80

We have investigated the regulation of transforming growth factor beta 1 gene expression in a variety of porcine immune cell populations, including peripheral blood mononuclear cells (PBMC), peripheral blood monocytes, alveolar macrophages and lymphoid cells from various swine lymphoid tissues. Using porcine transforming growth factor beta 1 cDNA probes in Northern blot assays, messages of 2.5 and 3.5 kb TGF beta 1 mRNA were detected in the cells investigated. A variety of mitogenic and immunomodulatory substances were examined for their ability to induce TGF beta 1 mRNA expression. These include phorbol 12-myristate 13-acetate (PMA), phytohemagglutinin (PHA), concanavalin A (Con A), lipopolysaccharide (LPS), dexamethasone (Dex), tumor necrosis factor (TNF) and interleukin (IL)-1 alpha. While low level constitutive expression of TGF beta 1 mRNA was detected from all cells investigated, PMA treatment of PBMC and alveolar macrophages resulted in a more than 10-fold increase in the steady-state level of TGF beta 1 mRNA within 2 hr of PMA addition. Also, the effect of opiate drugs, methadone (Md) and morphine (Mor), on TGF beta 1 gene expression was determined. Cells treated with opiates expressed the same levels of TGF beta 1 mRNA as untreated cells. Since TGF beta 1 biological activity can be induced by opiates, the regulation of TGF beta 1 gene expression likely involves mechanisms that do not cause changes in mRNA levels.
Mol Immunol
PMID:Characterization of transforming growth factor-beta 1 gene expression in porcine immune cells. 138 43

The biosynthesis of alternative regulatory complement protein factor H was investigated using both an in vivo rat model and an in vitro rat hepatocyte culture system, and compared to that of C3 component. Subcutaneous injection of a single dose of 20 micrograms of recombinant murine tumor necrosis factor-alpha (rmTNF-alpha) had no effect on factor H liver mRNA levels, while it increased C3 mRNA levels. In correlation with this, serum factor H levels remained unchanged after rmTNF-alpha injection, whereas C3 levels were increased. In contrast in vitro studies showed that rmTNF-alpha had no effect on factor H and C3 expression by rat hepatocytes. Recombinant human interleukin-1 alpha (rhIL-1 alpha) did not alter the expression of factor H, whereas it increased C3 expression, and recombinant human interleukin-6 (rhIL-6) stimulated expression of both proteins. This study shows that TNF-alpha is not directly responsible for the increased levels of factor H observed in vivo during induced inflammation in the rat. Its in vivo effect on C3 secretion might be secondary to the TNF-alpha-induced release of IL-1 and/or IL-6.
Mol Immunol
PMID:Differential modulation of complement factor H and C3 expression by TNF-alpha in the rat. In vitro and in vivo studies. 138 44

The mesothelium contains both procoagulant and fibrinolytic activities. An imbalance between these activities could account for the abnormal fibrin turnover and pleural fibrin deposition that is characteristic of pleural inflammation. Procoagulant activity of human pleural mesothelial cells (HPMC) is in part due to tissue factor, and the prothrombinase complex can also assemble at the HPMC surface. HPMC express tissue plasminogen activator (tPA) but no detectable fibrinolytic activity in a fibrin plate assay. Inhibition of HPMC fibrinolytic activity is due, in part, to elaboration of plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) as well as antiplasmins. Synthesis of PAI-1 and PAI-2 is inhibited by actinomycin D and cyclohexamide. HPMC PAI-1 is increased by transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha), as is tPA release, while PAI-1 mRNA is unchanged and tPA mRNA is increased. PAI-2 release is induced by TNF-alpha and TGF-beta. Because they are a rich source of PAI-1 and PAI-2, HPMC may contribute to the high levels of these inhibitors in pleural exudates. Stimulation of HPMC by TNF-alpha or TGF-beta in vitro did not alter HPMC procoagulant activity nor the balance of elevated PAI and antiplasmins relative to PA, changes that collectively favor formation and persistence of pericellular fibrin.
Am J Respir Cell Mol Biol 1992 Oct
PMID:Pathways of fibrin turnover of human pleural mesothelial cells in vitro. 138 10

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.
Mol Biother 1992 Sep
PMID:A gelonin-containing immunotoxin directed against human breast carcinoma. 144 65

1. Evidence for bidirectional interrelationships between the nervous system and immune systems of vertebrates and invertebrates involving opioid peptides is briefly discussed. 2. The involvement of opioid peptides in autoimmunoregulatory communication also is discussed. 3. The presence of mammalian interleukin-like (1 & 6) and tumor necrosis factor-like molecules in invertebrates is reviewed as well as an apparent cascading system for these signal molecules. 4. The significance of ACTH and MSH in cellular immunosuppression and autoimmunoregulation is discussed in the context of a potential role in schistosomiasis and human immunodeficiency virus actions. 5. The review concludes with the hypothesis that the mammalian immune system has its origin in the invertebrate immune/defense system given the many similarities noted in the review based on new knowledge about the more "primitive" system.
Cell Mol Neurobiol 1992 Oct
PMID:Invertebrate and vertebrate neuroimmune and autoimmunoregulatory commonalties involving opioid peptides. 146 13

Based on our new finding that an inflammation in which tumor necrosis factor (TNF) is primed or triggered (ontogenic inflammation) can regulate the homeostasis in ontogenesis, we have identified a new lipopolysaccharide from wheat flour (LPSw) that can induce ontogenic inflammation in adult mice. LPSw can prime adult mice to produce TNF when given orally or percutaneously, suggesting that it may maintain homeostasis in adults. LPSw can cure experimental animals of diabetes, hyperlipidemia, ulcer, and herpes. It can also stimulate bone resorption and egg-laying, and shows a strong analgesic effect that is blocked by naloxone. This effect even allows a release from drug addiction. Suppression of serum cholesterol level by oral uptake of LPSw in Watanabe heritable hyperlipidemic (WHHL) rabbit was also observed. Infection of toxoplasma was prevented by oral uptake of LPSw. The realization that a single oral or percutaneous administration of LPSw may be a cure for multiple intractable diseases may lead to the presentation of a nontoxic type of Coley's toxin, which is known to be an efficient cancer treatment, but has high toxicity.
Mol Biother 1992 Dec
PMID:Oral or percutaneous administration of lipopolysaccharide of small molecular size may cure various intractable diseases: a new version of Coley's toxin. 147 70

Antitumor effect of recombinant human tumor necrosis factor (TNF)-alpha lacking one to three amino acids from the N terminal part (TNFNv3) was tested for its antitumor effect on subcutaneous fibrosarcoma SA-1 tumors. Peritumoral treatment with 5 x 10(4) U TNFNv3 three times every second day significantly delayed tumor growth. Treatment with 10 times higher dose (5 x 10(5) U) produced 6.0 +/- 1.0 days tumor growth delay, but had side effects such as weight loss. The two new desmuramyl N-acyl dipeptides, LK-409 and LK-410, also exhibited such effect; however, the tumor growth delay was barely significant. The treatment was performed with two concentrations (2.5 micrograms and 25.0 micrograms) applied intraperitoneally for 5 consecutive days, without a dose-dependent effect. Combined treatment with TNFNv3 and desmuramyl dipeptides augmented the antitumor effect of treatments. The effect was additive and significant in the combination of 2.5 micrograms LK-410 with 5 x 10(5) U TNFNv3. LK-410 treatment also reduced the side effects of TNFNv3. The results indicate that combined treatment with both biological response modifiers is effective in tumor treatment.
Mol Biother 1992 Dec
PMID:Antitumor effect of recombinant human tumor necrosis factor-alpha analog combined with desmuramyl dipeptides LK-409 or LK-410 on sarcoma in mice. 147 73

Recent biochemical studies have suggested that apoptotic cell death is the molecular mechanism underlying the degeneration of ovarian follicles during atresia. Using a sensitive autoradiographic method for the detection of DNA fragmentation, we studied apoptosis in ovarian granulosa cells or intact follicles placed in serum-free culture as model systems to elucidate the hormonal regulation of atresia. Immature rats (25 days old) were primed for 2 days with 10 IU equine CG to induce a homogeneous population of mature preovulatory follicles. Granulosa cells isolated from these follicles contained predominantly intact high mol wt DNA. However, a time-dependent, spontaneous onset of internucleosomal DNA fragmentation characteristic of apoptotic cell death occurred in granulosa cells during culture. Treatment of granulosa cells with epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha), or basic fibroblast growth factor (bFGF) inhibited the spontaneous onset of apoptotic DNA cleavage found during culture by 40-60%. In contrast, insulin-like growth factor I, insulin, TGF beta and tumor necrosis factor-alpha were ineffective. Likewise, activation of the protein kinase A or C pathways with forskolin or phorbol 12-myristate 13-acetate, respectively, did not prevent the onset of DNA fragmentation, although inclusion of a tyrosine kinase inhibitor (genistein) completely blocked the ability of EGF, TGF alpha, and bFGF to suppress apoptosis in granulosa cells. Similar to cultured granulosa cells, a spontaneous onset of apoptosis was also observed to occur in isolated preovulatory follicles during culture. Furthermore, treatment of follicles with EGF or bFGF inhibited the spontaneous initiation of apoptosis, and the suppressive effects of these growth factors were also attenuated by co-treatment with genistein.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Nov
PMID:Epidermal growth factor and basic fibroblast growth factor suppress the spontaneous onset of apoptosis in cultured rat ovarian granulosa cells and follicles by a tyrosine kinase-dependent mechanism. 148 Jan 80

Lipopolysaccharide (LPS)-mediated synthesis of macrophage gene products such as tumor necrosis factor (TNF) is controlled by different signaling pathways. We investigated intracellular free Ca2+ (Ca2+ic) and the membrane potential as early cellular responses to LPS and their role in the synthesis and release of TNF. In peritoneal macrophages and in the RAW 269 mouse macrophage cell line, LPS and its biologically active moiety lipid A stimulated TNF synthesis but exerted no significant effects on these early cellular responses using Fura-2/Indo-1 to measure Ca2+ic and bis-oxonol, as well as the patch-clamp technique to monitor membrane potential. In contrast, the platelet-activating factor transiently induced both an increase in Ca2+ic and cell membrane depolarization but no significant TNF release. Increased extracellular K+ concentrations or K(+)-channel blockers, such as quinine, tetraethylammonium, or barium chloride, inhibited the LPS-stimulated release of TNF alpha, as well as the accumulation of cell-associated TNF alpha as found by enzyme-linked immunosorbent assay analysis, but did not inhibit TNF alpha mRNA accumulation. Concentrations of quinine (greater than 125 microM) or of enhanced extracellular K+ (25-85 mM) required to inhibit TNF production both significantly depolarized macrophages. These results indicate a lack of ion transport activities as early cellular responses of macrophages to LPS but suggest an important regulatory role of the membrane potential on the posttranscriptional synthesis and release of TNF in macrophages.
Mol Biol Cell 1992 Apr
PMID:Membrane potential modulates release of tumor necrosis factor in lipopolysaccharide-stimulated mouse macrophages. 149 65


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