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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All cells are constantly exposed to conflicting environment cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. In addition to survival factor withdrawal, cell death can be triggered by environmental stresses such as heat, UV light, and hyperosmolarity or by dedicated death receptors (e.g., FAS/APO-1 and tumor necrosis factor [TNF] receptors) that are counterparts of growth factor or survival receptors at the cell surface. One of the ways that cells integrate conflicting exogenous stimuli is by phosphorylation (or dephosphorylation) of cellular constituents by interacting cascades of serine/threonine and tyrosine protein kinases (and phosphatases). Survival factors (e.g., growth factors and mitogens) activate receptor tyrosine kinases and selected mitogen-activated, cyclin-dependent, lipid-activated, nucleic acid-dependent, and cyclic AMP-dependent kinases to promote cell survival and proliferation, whereas environmental stress (or death factors such as FAS/APO-1 ligand and TNF-alpha) activates different members of these kinase families to inhibit cell growth and, under some circumstances, promote apoptotic cell death. Because individual kinase cascades can interact with one another, they are able to integrate conflicting exogenous stimuli and provide a link between cell surface receptors and the biochemical pathways leading to cell proliferation or cell death.
Microbiol Mol Biol Rev 1997 Mar
PMID:Kinase cascades regulating entry into apoptosis. 910 63

There is evidence that nitric oxide (NO) may mediate some of the functional myocardial changes caused by bacterial LPS and inflammatory cytokines. The expression of the inflammatory or inducible NO synthase (iNOS) in human cardiac myocytes, however, has not been well characterized. Therefore, we treated cultured, dedifferentiated human ventricular cardiac myocytes with the combination of TNF-alpha (500 U/ml), IL-1beta (30U/ml), IFNgamma (100 U/ml), and LPS (E.coli 0111:B4, 10 microg/ml). Northern blot analysis revealed a approximately 4.5 kb transcript for inducible NOS (iNOS) in the stimulated human heart cells but not in untreated cells. RT-PCR confirmed that iNOS mRNA was only present in stimulated cells. However, treatment of the myocytes for up to 96 h with cytokines and LPS did not result in NO synthesis as measured by nitrite + nitrate accumulation in the culture medium, and no iNOS enzymatic activity could be detected in the cell lysates. Western blot analysis failed to detect iNOS protein. Thus, despite high and persistent levels of iNOS mRNA in cytokine-treated cells, iNOS protein was absent in this experimental model. GTP-cyclohydrolase I was induced both at the mRNA and protein levels and resulted in increased biopterin levels, indicating sufficient amounts of the cofactor tetrahydrobiopterin (BH4) were present, and that the failure to express an inducible protein was specific to iNOS. To determine if the absence of iNOS protein was due to a novel cardiac iNOS gene or modified iNOS transcript in human myocytes, we cloned an iNOS cDNA from cytokine-treated myocytes. Sequencing and expression of the clone revealed a functional iNOS cDNA with >99% identity to other human iNOS cDNA clones. When human cardiac cells were transduced with a retroviral vector carrying only the coding region of the human hepatocyte iNOS cDNA, both iNOS mRNA and protein could be detected. In conclusion, these cells derived from cultured human cardiac myocytes lacked the capacity to express an endogenous iNOS protein, the basis of which appears to be a cell-specific suppression or failure of iNOS translation.
J Mol Cell Cardiol 1997 Apr
PMID:Dedifferentiated human ventricular cardiac myocytes express inducible nitric oxide synthase mRNA but not protein in response to IL-1, TNF, IFNgamma, and LPS. 916 Aug 67

We evaluated the effects of cytokines on the catalytic activity and expression of porcine pulmonary artery endothelial cell (PAEC) constitutive (eNOS) and inducible (iNOS) isoforms of nitric oxide synthase (NOS). Exposure of PAEC to the combination of IFN-gamma, TNF-alpha, and IL-1 beta did not alter iNOS activity in cytosolic and membrane fractions but significantly (p < 0.01) reduced eNOS activity in the membrane fraction, but not in the cytosolic fraction, after a 24-h exposure. The cytokine-induced loss of membrane fraction eNOS activity was associated with significant reductions of eNOS mRNA and protein content (p < 0.01 for both). Treatment with the protein synthesis inhibitor, cycloheximide, but not the transcriptional inhibitor actinomycin D prevented cytokine-induced reduction of eNOS mRNA expression. These results suggest that cytokine-induced loss of catalytic activity of eNOS is associated with a reduction in eNOS mRNA and protein mass and that cytokines alter eNOS mRNA stability. Inhibition of protein synthesis prevented reduction of eNOS mRNA by cytokines, suggesting that the mechanism by which cytokines alter eNOS mRNA stability involves protein synthesis.
Res Commun Mol Pathol Pharmacol 1997 Apr
PMID:Proinflammatory cytokines downregulate gene expression and activity of constitutive nitric oxide synthase in porcine pulmonary artery endothelial cells. 917 69

We have used a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay to detect the expression of mRNA for inflammatory cytokines, integrins and selectins in murine lung tissue, and T cells and eosinophils isolated from lung and bronchoalveolar lavage (BAL) fluid in an in vivo model of ovalbumin (OA)-induced airway inflammation. RNA was isolated from whole lung tissue at 1, 6, 24, 48, 72 h, and 7 days after OA inhalation. mRNA for the Th2 cytokines, IL-4, -5, -6, -10 and -13 in OA-sensitized mice were significantly elevated compared with non-sensitized mice. IL-2, TNF-beta, and eotaxin mRNA were also increased, but IFN-gamma mRNA was not. P- and E-selectin mRNA levels were also enhanced in lung tissue between 6 and 72 h after challenge. Lung T cells were isolated by cell sorting with a flow cytometer at 3, 12, 24, 48 and 72 h after challenge. mRNA levels for IL-5 and -10 were greater in T cells from OA-sensitized and -challenged mice than controls at 24 h. BAL fluid from OA-sensitized and -challenged mice also had significantly higher IL-5 levels than controls. BAL fluid T cells and eosinophils were obtained at 48 and 72 h after aerosol challenge and were purified by cell sorting. Messenger RNA for IL-1 alpha, -2, -4, -5, -10, IFN-gamma, and beta 1 were detected in T cells at both time points. Transcripts for IL-1 alpha, -4, -5, -13, TNF-alpha and beta, and alpha 4, beta 1 and beta 7 were also identified in BAL eosinophils. These data show that in addition to murine lung T cells, airway eosinophils may also contribute to the inflammatory response by their ability to express mRNA for cytokines and integrins.
Am J Respir Cell Mol Biol 1997 Jun
PMID:Identification of cytokine and adhesion molecule mRNA in murine lung tissue and isolated T cells and eosinophils by semi-quantitative reverse transcriptase-polymerase chain reaction. 919 71

TNF-alpha induced sphingomyelin hydrolysis by sphingomyelinase and both sphingosine and ceramide generation have been reported to be implicated in a number of TNF-alpha responses, including cytotoxicity and apoptosis. We found that sphingosine, a highly cytotoxic product of enzymatic degradation of sphingomyelin, is accumulated in liver of mice treated with TNF-alpha. To determine the role of sphingosine in TNF-alpha toxicity, TNF-alpha mutants differing in their cytotoxicity to L929 cells as well as haemorrhagic tumor necrosis, tumor regression and lethal toxicity in mice were used in our experiments. The mutants with highest toxicity and tumor-necrotizing activity caused accumulation of sphingosine exceeded its control level 5,5 times in murine liver cells. TNF-alpha variants which caused moderate increase in sphingosine content were significantly less toxic. The observed relationship between toxicity of TNF-alpha mutants, the toxicity of sphingosine, and the extent of its accumulation in murine liver provides evidence to suggest that this sphingomyelin metabolite may be mediator of TNF-alpha-induced cell damage and death.
Biochem Mol Biol Int 1997 Jun
PMID:Relation of biological activity of mutant forms of recombinant human tumor necrosis factor alpha and accumulation of sphingosine in murine liver. 919 94

Adenosine and related analogs have been shown to regulate a variety of cell functions through different classes of adenosine receptors. Murine J774.1 macrophage cells were found to predominantly express adenosine A3 receptor RNA relative to adenosine A1 receptor or adenosine A2 receptor RNA. Adenosine receptor agonists, in a dose-dependent manner characteristic of the adenosine A3 receptor, blocked endotoxin-induction of the TNF-alpha gene and TNF-alpha protein expression in the J774.1 macrophage cell line. The adenosine A3 receptor antagonist BW-1433 dose-dependently reversed this adenosine receptor agonist inhibitory effect on TNF-alpha gene expression. Thus, the binding of adenosine receptor agonists to the adenosine A3 receptor interrupts the endotoxin CD14 receptor signal transduction pathway and blocks induction of cytokine TNF-alpha, revealing a novel cross-talk between the murine adenosine A3 receptor and the endotoxin CD14 receptor in J774.1 macrophages.
Cell Mol Biol (Noisy-le-grand) 1997 May
PMID:Adenosine A3 receptor agonists inhibit murine macrophage tumor necrosis factor-alpha production in vitro and in vivo. 919 89

Interleukin-8 (IL-8) is a chemoattractant and activating factor for human neutrophlls and a potent angiogenic agent. The peritoneal fluid of women with endometriosis has been shown to have increased neutrophil chemotactic activity. We postulate that IL-8 may be an important modulator in the pathogenesis of endometriosis and adhesion formation. We first investigated IL-8 concentrations in the peritoneal fluid of women with or without endometriosis, then assessed peritoneal mesothelial cells as a potential source of peritoneal fluid IL-8. Northern blot analysis and enzyme-linked immunosorbent assay (ELISA) were used to investigate IL-8 mRNA and protein modulation. The mean concentration of IL-8 in samples obtained from control patients (n = 28) was 4.8 +/- 0.5 pg/ml; from patients with minimal-mild endometriosis (n = 24) was 27.5 +/- 2.6 pg/ml; and from patients with moderate-severe endometriosis (n = 21) was 530.2 +/- 65.1 pg/ml. Confluent mesothelial cells were incubated with human recombinant IL-1 alpha (0.01-100 IU/ml) or tumour necrosis factor (TNF)-alpha (0.01 to 100 ng/ml) for 2-24 h. IL-8 mRNA was detectable in non-treated cells, however both IL-1 alpha and TNF-alpha induced higher amounts of IL-8 mRNA in a dose- and time-dependent manner. Non-treated mesothelial cells in culture also produced and secreted IL-8 protein quantified by ELISA, but again higher concentrations were induced by IL-1 alpha and TNF-alpha treatment. In conclusion, we found that IL-8 concentrations were elevated in peritoneal fluids from women with endometriosis. Cultured mesothelial cells expressed cytokine-inducible IL-8 mRNA and secreted IL-8 protein. The regulated expression of this angiogenic factor may play a role in pathogenesis of endometriosis.
Mol Hum Reprod 1996 Jan
PMID:Interleukin-8 concentration in peritoneal fluid of patients with endometriosis and modulation of interleukin-8 expression in human mesothelial cells. 923 56

The infiltration of leukocytes is a characteristic feature of luteolysis in humans. Leukocytes are known to generate physiological inducers of cell stress such as cytokines which have been implicated as mediators of functional luteal regression. In cells exposed to stress, a response characterized by an increase in heat shock protein (HSP) synthesis occurs. Recently, the induction of HSP-70 in rat luteal cells has been shown to inhibit luteinizing hormone (LH) and cAMP-sensitive progesterone production, possibly by interfering with the translocation of cholesterol to the mitochondrial cytochrome P450scc. We therefore investigated whether HSP-70 is induced in human granulosa-luteal cells and its relationship to steroidogenesis. [35S]Methionine labelling showed an increase in a 70 kDa protein after heat treatment which was demonstrated to be HSP-70 by Western analysis using monoclonal antibodies against the constitutive and inducible forms of HSP-70. Induction of HSP-70 in human granulosa-luteal cells was also seen with interferon (IFN) gamma (10 ng/ml), tumour necrosis factor (TNF)-alpha (100 ng/ml) and a combination of IFN gamma/TNF-alpha (10/50 ng/ml). Interleukin-1 beta (IL-1 beta) (30 ng/ml) showed minimal induction of HSP-70 above control values. An increase in activated heat shock factor, which binds to the heat shock transcriptional control element, was detected after heat shock, IFN/TNF, and IFN treatment. Coincident with the induction of HSP-70 by heat shock was the inhibition of progesterone production compared with non-shocked granulosa-luteal cells. Heat shock inhibition of progesterone synthesis was partially reversed by the cell- and mitochondria-permeant cholesterol analogue, 22R-hydroxycholesterol. Cell viability was unaffected by heat treatment. White blood cell-depleted granulosa-luteal cell cultures treated with IFN demonstrated a significant reduction in progesterone production. Treatment with IFN/TNF, TNF, and IL-1 also decreased progesterone secretion, although statistical significance was not achieved. These findings provide evidence that a stress response occurs in human granulosa-luteal cells in response to heat and cytokines. The inhibition of gonadotrophin-sensitive steroidogenesis coincident with the induction of HSP-70 synthesis by physiological agents which are present in the corpus luteum implicates HSP-70 as a potential mediator of luteolysis in the human.
Mol Hum Reprod 1996 Aug
PMID:Cytokine induction of heat shock protein in human granulosa-luteal cells. 923 66

When macrophages were cultured with lactoferrin, cytokines such as tumor necrosis factor (TNF-alpha), interleukin 8 (IL-8) and nitric oxide (NO) were secreted. Secretion of TNF-alpha peaked at 6 h of incubation in the presence of lactoferrin and then declined. About 80% of the maximum secretion of IL-8 was observed at 6 h of incubation. The concentration of IL-8 in the culture medium remained almost constant between 24-72 h. In contrast, no significant effect on NO secretion was observed at 6 h, but a significant effect was observed at 24 h and secretion gradually increased between 24-72 h. The effects of lactoferrin on the secretion of TNF-alpha, IL-8 and NO were dose-dependent and lactoferrin had a significant effect on secretion of at concentrations greater than 10 mg/ml. The use of reverse transcription-polymerase chain reaction (RT-PCR) showed that the results obtained were consistent with the cytokine secretion results. It is concluded that lactoferrin activates macrophages which result in the secretion of TNF-alpha, IL-8 and NO.
Biochem Mol Biol Int 1997 Sep
PMID:Activation of macrophages by lactoferrin: secretion of TNF-alpha, IL-8 and NO. 931 85

There is increasing evidence that locally produced cytokines may play an important role in the control of testicular function. In a previous report we demonstrated that medium conditioned by activated human peripheral blood mononuclear cells (PBMC-CM), which is a rich source of cytokines, has extremely potent effects on Sertoli cell transferrin and cGMP secretion. Part of this activity could be explained by interleukin-1beta (IL-1beta) but additional cytokines were evidently involved. In the present study we tried to characterize and purify additional components active on Sertoli cells from PBMC-CM. To this end PBMC-CM was subjected to a purification procedure involving successively: adsorption to silicic acid, affinity chromatography with an antiserum recognizing a mixture of cytokines except IL-1beta, gel-filtration, reversed-phase HPLC and cation-exchange FPLC. Throughout this protocol a Sertoli cell bioassay was used to monitor the effects on transferrin and cGMP production. After cation-exchange FPLC, SDS-PAGE using silver staining showed a single protein band in the bioactive fractions. NH2-terminal amino-acid sequencing revealed that the active principle(s) in this band corresponded to four truncated forms of IL-6 missing the first 13, 14, 17 and 18 N-terminal amino-acids, respectively. The truncated IL-6 molecules were as active as intact IL-6 in the Sertoli cell bioassay. Since neither IL-1beta nor IL-6 alone or in combination could account for the extremely potent effect of PBMC-CM, we tested a series of additional cytokines (IL-1alpha, INF-alpha, IL-4, TGF-beta, IFN-gamma) alone and in combination with IL-1beta and IL-6. These data suggest that IL-1beta, IL-6 and TNF-alpha display more than additive effects on Sertoli cell transferrin and cGMP secretion and that the combination of these cytokines may explain the major part of the effects observed with crude PBMC-CM. The observation that the latter effects could be observed with murine as well as human IL-1beta, IL-6 and TNF-alpha further supports the potential physiological relevance of these findings.
Mol Cell Endocrinol 1997 Sep 19
PMID:Identification of IL-6 as one of the important cytokines responsible for the ability of mononuclear cells to stimulate Sertoli cell functions. 932 56


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