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)

This work was designed to study the proliferative response of tumor-associated lymphocytes (TAL) from neoplastic effusions against autologous tumor cells and the immunophenotype pattern of TAL from neoplastic effusions and that of PBMC of the same patients. We also compared the serum levels of the cytokines interleukin (IL) 1 beta, 2 and 6, tumor necrosis factor-alpha (TNF alpha) and soluble IL-2 receptor (sIL-2R) with those present in neoplastic effusions of the same patients. Moreover, we examined the ability of TAL and peripheral blood mononuclear cells (PBMC) to produce and release the cytokines and sIL-2R and to express membrane CD25 following their stimulation with phytohemagglutinin (PHA) in vitro. Finally, we compared the cytokines/sIL-2R production and membrane CD25 expression by PHA-stimulated PBMC of the patients with neoplastic effusions with a series of 90 cancer patients without neoplastic effusions and 20 normal healthy subjects. Thirteen neoplastic pleural and eight peritoneal effusions were collected from 11 patients with primary lung cancer, 7 with primary epithelial ovarian cancer, 1 with breast cancer, 1 with pleural mesothelioma, and 1 with pancreatic cancer. The proliferative response of TAL from neoplastic effusions against autologous tumor cells was lower than the response to PHA, IL-2, and anti-CD3, but significant. The percentage distribution of CD3+ and CD8+ lymphocyte subpopulations was higher in peritoneal than in pleural effusions, while the CD16+ subset was higher in pleural than in peritoneal effusions. The percentage distribution of CD16+ was significantly lower in pleural effusions than in PBMC of patients with pleural effusions.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Med (Berl) 1995 Aug
PMID:Tumor-associated lymphocytes (TAL) are competent to produce higher levels of cytokines in neoplastic pleural and peritoneal effusions than those found in sera and are able to release into culture higher levels of IL-2 and IL-6 than those released by PBMC. 852 43

Synthesis of the biologically active oestrogen, oestradiol, within breast tumours makes an important contribution to the high concentrations of oestrogens which are present in malignant breast tissues. In breast tumours, oestrone is preferentially converted to oestradiol by the Type I oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH). Several growth factors, such as insulin-like growth factor Type I, and cytokines, such as Tumour Necrosis Factor alpha (TNF alpha), have been shown to stimulate E2DH activity in MCF-7 breast cancer cells. As little is known about the regulation of Type I E2DH expression and activity in other breast cancer cell lines, the expression and activity of this enzyme was examined in other oestrogen receptor positive and also oestrogen receptor negative breast cancer cell lines. As it is possible that E2DH activity may be limited by co-factor availability, the effects of exogenous co-factors on enzyme activity in these cell lines was also investigated. For T47D and BT20 breast cancer cells, the addition of exogenous co-factors was found to enhance enzyme activity. TNF alpha, in addition to stimulating E2DH activity in MCF-7 cells, also increased activity in T47D and MDA-MB-231 cells, although to a lesser extent than in MCF-7 cells. An investigation of signalling pathways involved in the regulation of E2DH activity revealed that stimulation of both the protein kinase C (PKC) and PKA pathways may be involved in regulation of E2DH activity. As several growth factors and cytokines have now been found to be involved in regulating E2DH activity, the role that macrophages and lymphocytes have in supplying these factors and the mechanism by which these factors may stimulate tumour growth, is also reviewed.
J Steroid Biochem Mol Biol 1995 Dec
PMID:The role and proposed mechanism by which oestradiol 17 beta-hydroxysteroid dehydrogenase regulates breast tumour oestrogen concentrations. 854 83

We previously showed that intra-arterial endotoxin infusion (lipopolysaccharide [LPS]: 25 micrograms.kg-1) induced an early (15 min) and sustained (480 min) rise in plasma ACTH associated with delayed (60-120 min) increases in plasma concentrations of TNF alpha, IL-6, and IL-1 beta. In the present study, we followed the post-LPS time-course of immunocytochemical expression of Fos-like activity in CRH41 neurons whose immunolabeling was enhanced by icv colchicine pretreatment 48 h before the LPS, and CRH41 release in the push-pull cannulated median eminence of free-moving rats, in parallel with the ACTH response. The earliest Fos-like activity in IR-CHR41 neurons was detected 30 min post-LPS. Colchicine strongly inhibited the LPS-induced activation of Fos expression in single-labeled paraventricular neurons. CRH41 release in the median eminence displayed a biphasic stimulation pattern, with a first peak (+60%) at 15 min together with the ACTH surge, followed by a second rise beginning at 45 min and lasting more than 2 h. Thus, the early stage of the ACTH surge following a nonlethal endotoxin challenge (< 60 min) already involves the activation of CRH41-producing neurons.
Mol Chem Neuropathol 1995 Oct
PMID:Early hypothalamic activation of combined Fos and CRH41 immunoreactivity and of CRH41 release in push-pull cannulated rats after systemic endotoxin challenge. 857 42

In addition to biophysical properties, pulmonary surfactant has immunomodulatory activity. We previously demonstrated that both synthetic (Exosurf) and modified natural surfactant (Survanta) downregulated endotoxin-stimulated inflammatory c ytokine mRNA levels and protein products (tumor necrosis factor-alpha [TNF], interleukin-1-beta [IL-1], interleukin-6 [IL-6]) in human alveolar macrophages. In this study, we report that both Exosurf and Survanta suppress TNF mRNA and secretion (85 +/- 4% mean percent inhibition +/- SEM by Exosurf; 71 +/- 6% by Survanta) by endotoxin-stimulated THP-1, a human monocytic cell line. Because surfactant downregulated inflammatory cytokine production similarly in both normal human alveolar macrophages and the THP-1 cell line, we used this cell line to investigate whether surfactant affected transcriptional mechanisms. Specifically, we examined nuclear factor-kappa B (NF-kappa B) activation because it is crucial in transcriptional regulation of many inflammatory cytokine genes including TNF, IL-1, and IL-6. Electrophoretic mobility shift assays showed that both surfactants decreased activation of NF-kappa B. The presence of both p65 and p50 NF-kappa B components in LPS-activated THP-1 cells was confirmed by specific antibody induction of supershifts in mobility assays. These results are the first to suggest that surfactant's suppressive effects on inflammatory cytokine production may involve transcriptional regulation through inhibition of NF-kappa B activation.
Am J Respir Cell Mol Biol 1996 Apr
PMID:Surfactant suppresses NF-kappa B activation in human monocytic cells. 860 Sep 42

We explored the effects of cytokines on cytochrome P-450 (CYP) in rat hepatocyte primary cultures. CYP content and several CYP protein levels were assessed in hepatocytes treated with a cytokine combination consisting of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN gamma). The combination was found to depress CYP content by 69 +/- 6%. Protein levels of CYP forms 1A2, 2C11, 2B1/2, and 3A2 were assessed with immunoblotting. Treatment with the cytokine combination resulted in a decrease in each CYP enzyme, with CYP2B1/2 exhibiting the greatest loss, to 33 +/- 9% of untreated cells. The addition of inhibitors of nitric oxide synthase (NOS) significantly prevented the cytokine-mediated decrease in each CYP protein, indicating a role for nitric oxide (NO) in the down-regulation. Treatment of hepatocytes with the NO donor 1-hydroxy-2-oxo-3,3-bis(3-aminoethyl)-1-triazene (300 microM) caused a decrease in each CYP apoprotein, with CYP2B1/2 exhibiting the greatest decrease, to 33 +/- 8% of untreated cells. Decreases in CYP protein levels were observed in response to treatment with TNF alpha, IL-1 beta, or IL-6 alone. With IL-1 beta treatment, increased levels of NO production were accompanied by decreased levels of each CYP protein. With TNF alpha treatment, increased levels of NO production were accompanied by decreased levels of CYP2B1/2 and CYP3A2. The effects of IL-1 beta and TNF alpha were blocked by the inclusion of the NOS inhibitors. Conversely, IL-6 caused a decrease in each of the CYP enzymes but did not affect NO production. The results indicate a dissociation in vitro between NOS induction and CYP down-regulation for IL-6 treatment, whereas the down-regulation of CYP by TNF alpha and IL-1 beta in vitro is directly associated with NO production.
Mol Pharmacol 1996 May
PMID:Role of nitric oxide in the cytokine-mediated regulation of cytochrome P-450. 862 28

We have previously isolated by expression/selection cloning plasmids containing human cDNAs that rendered MCF-7 breast cancer cells resistant to immunotoxins, Pseudomonas exotoxin (PE), and diphtheria toxin (DT) [Brinkmann et al. (1995) Mol. Med. 1, 206-216]. Here we describe that one of these resistant plasmids, which contains an antisense cDNA fragment homologous to the yeast chromosome segregation gene CSE1 [CAS; Brinkmann et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10427-10431], reduces the intracellular content of the human CSE1 homologue CAS protein. CAS reduction confers resistance not only to the ADP-ribosylating toxins PE and DT, but also to tumor necrosis factor alpha and beta. The resistance was observed as reduced apoptosis. CAS antisense did not affect the cell death induced by staurosporine, cycloheximide, or etoposide. The observation that CAS antisense can interfere with apoptosis mediated by TNF and ADP-ribosylating toxins suggests that CAS may play a role in selected pathways of apoptosis.
 ...
PMID:Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis. 863 41

Alveolar-capillary membrane remodeling, including microvessel wall thickening and interstitial fibrosis, is a well-known sequela of cell proliferation in the hyperoxia-injured lung. The array of growth molecules released locally that potentially mediate this response, and their cell(s) of origin, are currently being defined. To elucidate the role of tumor necrosis factor alpha (TNF alpha), an effector molecule of cell injury and proliferation, and the role of the alveolar macrophage (AM) as its source during the acute (1 to 24 h) and chronic stages (3 to 28 days) of hyperoxia-induced injury, we have analyzed gene and protein expression in cells recovered from rat lung by bronchoalveolar lavage. In the hyperoxic lung, cell number was similar to that in normal lung (1 x 10(6)) except on day 7, when it was higher (5 x 10(6)). Virtually all cells recovered from the normal and hyperoxic lung were AMs, with the exception that on days 3 and 7 of hyperoxia these cells represented 69% and 55% of the population, respectively, and polymorphonuclear leukocytes and lymphocytes the remainder. Probe specificity was confirmed by detection of TNF alpha RNA (1.6 kb) from lung cells recovered after lipopolysaccharide (LPS) treatment (positive control) and from the hyperoxic lung (at day 3), with an extremely low level of constitutive expression detected in cells from normal lung. In cytospin preparations, TNF alpha mRNA transcripts were detected in few AMs recovered from normal lung and in most AMs after LPS treatment. In the hyperoxic lung, a signal was detected at 3 h, when approximately 25% of the population was positive. The number of hybridizing cells then increased, being highest on day 7 (day 1 approximately 30%, day 3 approximately 58%, day 7 approximately 90%, day 28 approximately 65%). No expression of TNF alpha protein was detected in AMs from normal lung; positive cells were detected in the hyperoxic lung from day 1 and thereafter. We conclude from upregulation of the TNF alpha gene in a significant number of cells, and from the increase in the number expressing biologically active protein, that AMs are an important source of this molecule both in the acute and chronic stages of hyperoxic lung injury. It is anticipated that an increased understanding of the cellular sources of mediators effecting vascular and alveolar wall remodeling in vivo will contribute to the development of strategies to inhibit the response.
Am J Respir Cell Mol Biol 1996 Jun
PMID:TNF alpha gene and protein expression in alveolar macrophages in acute and chronic hyperoxia-induced lung injury. 865 83

Histamine was one of the first inflammatory mediators thought to be important in the pathophysiology of asthma, but it is not now thought to be a mediator with primary importance in airway constriction. However, histamine has several effects that may be relevant. One of these effects, its immunoregulatory role, has been largely ignored in asthma. Thus, because mast cells (MC) are an important source of histamine and cytokines, the modulation by histamine of the release of one cytokine, tumor necrosis factor alpha (TNF alpha), was investigated. Rat peritoneal MC (PMC) were pretreated with different concentrations of histamine (10(-14) to 10(-4) M) for 2 h before being tested for their TNF alpha-dependent cytotoxicity. A concentration-dependent inhibition of cytotoxicity was observed from 21% at 10(-12) M to 38% at 10(-4) M, reaching a plateau at 10(-8) M. At least 1 h pretreatment with histamine or its presence throughout the cytotoxic assay was required for the inhibitory effect of histamine. This inhibition was abrogated by indomethacin or anti-PGE2, suggesting that PGE2 may be an important mediator in the inhibition of TNF alpha by histamine. To investigate the type of histamine receptor implicated in this effect, PMC were treated for 20 min with H1 (clemastine and diphenhydramine), H2 (ranitidine and cimetidine), or H3 (thioperamide) receptor antagonists before the addition of histamine. H2 or H3 antagonists abrogated the inhibitory effect of histamine on PMC TNF alpha-dependent cytotoxicity. Furthermore, blockage of H2 receptors with ranitidine increased the release of TNF alpha from PMC stimulated with antigen, suggesting that histamine released by MC within 10 min of antigen stimulation downregulates the subsequent release of TNF alpha from the same MC population. These results suggest that histamine may act as an autocrine regulator of cytokine release by MC and thus modulate inflammatory responses in allergic asthma.
Am J Respir Cell Mol Biol 1996 Jun
PMID:Histamine inhibits tumor necrosis factor alpha release by mast cells through H2 and H3 receptors. 865 90

Tumor necrosis factor alpha (TNF alpha) is a potentially important cytokine in allergic respiratory reactions since it is released by mast cells and eosinophils, and it can promote mediator and cytokine release, adhesion molecule expression, and granulocyte migration. Therefore, we induced an IgE-mediated response in human lung samples and studied: (1) whether TNF alpha was produced in sufficient quantities to promote granulocyte migration; and (2) which cells expressed mRNA for TNF alpha using in situ hybridization. Lung fragments (from thoracotomy) were treated for 30 min with either anti-IgE, 1:100 dilution, or buffer (control). Anti-IgE treatment of 16 lungs resulted in greater than 4-fold increase in histamine release and the significant production of chemotactic activity. The chemotactic activity generated induced dose-responsive neutrophil and eosinophil migration through naked filters and endothelial and pulmonary epithelial monolayers. Fourteen of 16 samples had a significant increase in TNF alpha subsequent to anti-IgE treatment (P < 0.05). Anti-TNF alpha antibody (4 micrograms/ml) inhibited about 25% of the neutrophil chemotactic activity in supernatants from anti-IgE treated lungs. TNF alpha at a concentration measured after anti-IgE treatment of lung samples (50 pg/ml) induced neutrophil transendothelial migration. Finally, we found that anti-IgE treatment led to an increase in TNF alpha mRNA-positive cells by in situ hybridization (1.6/ mm2 experimental versus 0.5/mm2 control), some of which were eosinophils. Thus, human lung IgE-mediated responses in vitro results in: (1) release of TNF alpha in amounts sufficient to effect a biologic response, granulocyte chemotaxis: and (2) upregulation of mRNA for TNF alpha in eosinophils and other cells. These findings suggest that TNF alpha is an important effector molecule in the pathogenesis of allergic respiratory reactions.
Am J Respir Cell Mol Biol 1996 Jul
PMID:TNF alpha is important in human lung allergic reactions. 867 20

Evidence suggests that cytokines may modulate smooth muscle cell function in a variety of inflammatory diseases. In the present study, we characterized the specific receptor subtypes that mediate tumor necrosis factor alpha (TNF alpha) effects on myocyte proliferation and on agonist-induced calcium transients in cultured human tracheal smooth muscle cells (TSMC). Pretreatment of human TSMC with TNF alpha potentiated cytosolic calcium [(Ca2+)i] transients evoked by carbachol. In a similar manner, selective TNF alpha-p55 receptor agonists such as htr-9, an activating monoclonal antibody, or a recombinant TNF-p55 (rTNF-p55), which specifically activates the TNF alpha-p55 receptor but not the TNF alpha-p75 receptor, also augmented [Ca2+]i transients evoked by carbachol. In parallel experiments, TNF alpha, rTNF alpha-p55, and htr-9 induced human TSMC proliferation as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Interestingly, activation of the TNF alpha-p75 receptor with a selective agonist, recombinant TNF alpha-p75 (rTNF alpha-p75), or inhibition of the TNF alpha-p75 receptor with utr-1, an inhibitory anti-TNF alpha-p75 receptor antibody, had no effect on TNF alpha-augmented calcium transients or on myocyte growth. To further confirm the receptor specificity of these findings, immunocytochemical studies were performed using receptor-specific antibodies. These studies demonstrated marked cell-surface expression of the TNF alpha-p55 receptor compared with expression of the TNF alpha-p75 receptor on human TSMC. Taken together, our results suggest that TNF alpha modulates agonist-induced calcium transients and induces human TSMC proliferation by specific activation of the TNF alpha-p55 receptor. Further studies addressing the cellular and molecular mechanisms regulating cytokine modulation of airway smooth muscle function may provide new insight into mechanisms that induce airway hyperresponsiveness in asthma.
Am J Respir Cell Mol Biol 1996 Jul
PMID:Activation of the TNF alpha-p55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle cells. 867 22


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