Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently shown that transforming growth factor-beta (TGF beta) acts in an autocrine manner to maintain the beating rate of neonatal rat cardiac myocytes cultured in serum-free medium on cardiac fibroblast matrix. Interleukin-1 beta (IL-1 beta) suppresses the myocyte-beating rate, and TGF beta antagonizes this effect. We now show that TGF beta and IL-1 beta also have antagonistic effects on the secretion of nitric oxide (NO) by these myocytes, and that NO secretion, the activity of NO synthase (NOS), and expression of the inducible form of NOS correlate inversely with the effects of these two agents on the beating rate. Western blot analysis shows that treatment of myocytes with TGF beta antagonizes the induction of NOS after treatment with IL-1 beta. Release of NO, induced by IL-1 beta, is dependent upon the availability of the substrate, L-arginine, and is suppressed by a competitive inhibitor, NG-monomethyl-L-arginine. L-Arginine (> 0.25 mM) also suppresses, and NG-monomethyl-L-arginine (> 0.5 mM) enhances the myocyte-beating rate. Treatment with IL-1 beta, but not TGF beta, increases cellular cGMP, presumably by activation of guanylate cyclase by NO. Methylene blue, an inhibitor of guanylate cyclase, reverses the suppression of beating caused by IL-1 beta. Bacterial lipopolysaccharide, present in the serum-free medium, is a coinducer of NO secretion. The suppressive effects of NO on the beating rate can be overcome by altering either the set of cytokines employed to induce NO or the matrix on which the myocytes are cultured, demonstrating that additional parameters are also involved in regulation of the beating rate.
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PMID:Role of nitric oxide in antagonistic effects of transforming growth factor-beta and interleukin-1 beta on the beating rate of cultured cardiac myocytes. 128 74

Lymphokine directed isotype switching is preceded by the induced expression of the corresponding germline Ig heavy chain constant region (CH) gene. This association favors a model in which lymphokine induced germline CH gene expression promotes switch recombination by increasing the accessibility of the switch region to a recombinase(s). An important prediction of this model is that the induction of germline CH RNAs represents increased specific de novo transcription. To test if this prediction is fulfilled by the switch commitment factors, IL-4 and transforming growth factor-beta (TGF-beta), we have utilized a B cell line, 1.29, that switches from IgM to IgE and IgA in vitro. In this cell line, IL-4 and TGF-beta increase germline C epsilon and C alpha RNA levels respectively, predominantly by elevating transcription of these genes. Transcription of germline C epsilon and C alpha genes appears to be independently regulated and is not affected by lipopolysaccharide or IL-5. These results are discussed in the context of the molecular events necessary to commit a B cell to an isotype switch.
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PMID:Transcriptional regulation of the germline immunoglobulin C alpha and C epsilon genes: implications for commitment to an isotype switch. 136 52

The rate of carbohydrate flux through phosphofructokinase (measured as the rate of [3-3H]glucose detritiation) was increased fourfold in rat liver parenchymal cells incubated with conditioned medium from lipopolysaccharide-stimulated adherent liver non-parenchymal cells. The rate was not affected in parenchymal cells incubated either with lipopolysaccharide directly or with conditioned medium from non-stimulated non-parenchymal cells. The stimulation of carbohydrate flux through phosphofructokinase by conditioned medium was not duplicated by peptide cytokines known to be released by lipopolysaccharide-activated liver non-parenchymal cells (interleukin-1, interleukin-6, tumor necrosis factor-alpha, and transforming growth factor-beta) or platelet activating factor. Furthermore, formation of the active conditioned medium was not prevented by inclusion of cycloheximide or dexamethasone to inhibit cytokine synthesis, or indomethacin or BW755c to inhibit arachidonic acid metabolism, during lipopolysaccharide-stimulation of the non-parenchymal cells. The results indicate that intercellular communication between lipopolysaccharide-stimulated liver non-parenchymal cells and parenchymal cells by soluble mediators is responsible for the stimulation of liver phosphofructokinase activity during endotoxin-induced shock. Studies to isolate and identify the factor(s) in the conditioned medium are currently in progress.
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PMID:Endotoxin stimulation of liver parenchymal cell phosphofructokinase activity requires nonparenchymal cells. 153 Nov 95

The influence of cytokines on extracellular superoxide dismutase (EC-SOD) expression by human dermal fibroblasts was investigated. The expression was markedly stimulated by interferon-gamma (IFN-gamma), was varying between fibroblast lines stimulated or depressed by interleukin-1 alpha (IL-1 alpha), was intermediately depressed by tumor necrosis factor-alpha (TNF-alpha), and markedly depressed by transforming growth factor-beta (TGF-beta). TNF-alpha, however, enhanced the stimulation by a high dose of IFN-gamma, whereas TGF-beta markedly depressed the stimulations given by IFN-gamma and IL-1 alpha. The ratio between the maximal stimulation and depression observed was around 30-fold. The responses were generally slow and developed over periods of several days. There were no effects of IFN-alpha, IL-2, IL-3, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, human growth hormone, Escherichia coli lipopolysaccharide, leukotriene B4, prostaglandin E2, formylmethionylleucylphenylalanine, platelet-activating factor, and indomethacin. The cytokines influencing the EC-SOD expression are also known to influence superoxide production by leukocytes and other cell types, and the EC-SOD response pattern is roughly compatible with the notion that its function is to protect cells against extracellular superoxide radicals. The results show that EC-SOD is a participant in the complex inflammatory response orchestrated by cytokines. The CuZn-SOD activity of the fibroblasts was not influenced by any of the cytokines, whereas the Mn-SOD activity was depressed by TGF-beta. TNF-alpha, IL-1 alpha, and IFN-gamma stimulated the Mn-SOD activity, as previously known, and these responses were reduced by TGF-beta. The different responses of the three SOD isoenzymes illustrate their different physiological roles.
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PMID:Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts. 155 78

Opiates modulate a variety of immune responses by peripheral blood mononuclear cells (PBMC). In the present study, we investigated the effect of morphine on the release of several cytokines upon stimulation with mitogens. An interleukin (IL)-4-dependent HT-2 cell proliferation assay was used to quantify transforming growth factor-beta (TGF-beta). IL-6 and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assays. Morphine (1 pM and 10 nM) alone did not significantly modulate the release of TGF-beta, IL-6 or TNF-alpha. Upon stimulation with lipopolysaccharide and phytohemagglutinin, PBMC released more (P less than .01) TGF-beta, IL-6 and TNF-alpha than unstimulated PBMC. Exposure of PBMC to morphine (1 pM) for 24 hr substantially amplified (P less than .05) the release of TGF-beta in the following 24 hr incubation period. Morphine did not alter the release of immunodetectable IL-6 or TNF-alpha from stimulated cells. The amplifying effect of morphine on the release of TGF-beta was mediated through a naloxone-sensitive mechanism. Given the fact that TGF-beta has a potent immunosuppressive effect, morphine-potentiated release of TGF-beta from PBMC may be involved in the immunomodulatory activity ascribed to morphine.
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PMID:Morphine potentiates transforming growth factor-beta release from human peripheral blood mononuclear cell cultures. 162 99

A method for the culturing and propagation of ovine bone marrow-derived macrophages (BMM) in vitro is described. Bone marrow cells from sterna of freshly slaughtered sheep were cultured in hydrophobic (teflon foil) bags in the presence of high serum concentrations (20% autologous serum and 20% fetal calf serum). During an 18 day culture period in the absence of added conditioned medium, and without medium change, a strong enrichment of mononuclear phagocytes was achieved. Whereas the number of macrophages increased four to fivefold during this time, granulocytes, lymphoid cells, stem cells and undifferentiated progenitor cells were reduced to less than 3% of their numbers at Day 0. This resulted in BMM populations of 94 +/- 3% purity. These cells had morphological and histochemical characteristics of differentiated macrophages, and they performed functions similar to those of non-activated, unprimed human monocyte-derived macrophages. Thus, they avidly ingested erythrocytes coated with IgG of heterologous or homologous origin. They expressed a modest level of procoagulant activity, but upon triggering with lipopolysaccharide (LPS), a marked increase in cell-associated procoagulant activity was observed. LPS triggering promoted the secretion of interleukin-1, as evidenced by measurement of murine thymocyte costimulatory activity, and transforming growth factor-beta. Using the mouse L929 cell cytotoxicity assay as an indication of tumor necrosis factor (TNF) activity, no TNF activity was detected in the same supernatants, a result possibly due to species restriction. BMM generated low levels of O2- upon triggering with phorbol 12-myristate 13-acetate (PMA). On the other hand, no O2- production was observed upon stimulation with zymosan opsonized with ovine or human serum. Using luminol-enhanced chemiluminescence (CL) as a more sensitive indicator of an oxidative burst, both PMA or zymosan were able to trigger CL, but the response was subject to partial inhibition by sodium azide, an inhibitor of myeloperoxidase. This points to non-macrophage cells contributing also to the CL response, and is consistent with the view that unprimed BMM elicit a low oxidative burst upon triggering with strong inducers of a burst. Our functional characterization now allows us to apply priming and activation protocols and to relate their effect to functional alterations.
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PMID:Generation and functional characterization of ovine bone marrow-derived macrophages. 163 66

The role of bacteria in the initiation of periodontitis is well-documented and the end result, destruction of the alveolar bone and periodontal connective tissue, is readily observed; but the events occurring between these two points in time remain obscure and are the focus of this paper. Bacteria induce tissue destruction indirectly by activating host defense cells, which in turn produce and release mediators that stimulate the effectors of connective tissue breakdown. Components of microbial plaque have the capacity to induce the initial infiltrate of inflammatory cells including lymphocytes, macrophages, and PMNs. Microbial components, especially lipopolysaccharide (LPS), have the capacity to activate macrophages to synthesize and secrete a wide array of molecules including the cytokines interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-alpha), prostaglandins, especially PGE2, and hydrolytic enzymes. Likewise, bacterial substances activate T lymphocytes and they produce IL-1 and lymphotoxin (LT), a molecule having properties very similar to TNF-alpha. These cytokines manifest potent proinflammatory and catabolic activities, and play key roles in periodontal tissue breakdown. They induce fibroblasts and macrophages to produce neutral metalloproteinases such as procollagenase and prostromelysin, the serine proteinase urokinase-type plasminogen activator (u-PA), tissue inhibitor of metalloproteinase (TIMP), and prostaglandins, u-PA converts plasminogen into plasmin, which can activate neutral metalloproteinase proenzymes, and these enzymes degrade the extracellular matrix components. TIMP inactivates the active enzymes and thereby blocks further tissue degradation. Several amplification and suppression mechanisms are involved in the process. While LPS activates macrophages to produce IL-1, IL-1 is autostimulatory and can therefore amplify and perpetuate its own production. Interferon-gamma (INF-gamma) suppresses autostimulation, but it enhances LPS-induced IL-1 production. PGE2 exerts a control over the whole process by suppressing production of both IL-1 and TNF-alpha. Furthermore, the activated cells produce an IL-1 receptor antagonist that binds to the IL-1 receptor but does not induce the biologic consequences of IL-1 binding. Other cytokines such as transforming growth factor-beta (TGF-beta) suppress production of metalloproteinases and u-PA. Thus the progression and extent of tissue degradation is likely to be determined in major part by relative concentrations and half-life of IL-1, TNF-alpha, and related cytokines, competing molecules such as the IL-1 receptor antagonist, and suppressive molecules such as TGF-beta and PGE2. These molecules control levels of latent and active metalloproteinase and u-PA, and the availability and concentration of TIMP determines the extent and duration of degradative activity.
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PMID:The role of inflammatory mediators in the pathogenesis of periodontal disease. 167 30

Cultured human keratinocytes and squamous cell carcinoma (SCC) cell lines were analyzed for the presence of ribonucleic acid (RNA) transcripts for the cytokines interleukin-1 and interleukin-6 and for these proteins. This study demonstrates that both cytokines are synthesized and secreted by both normal keratinocytes and SCC lines. The rate of secretion of these cytokines can be augmented in response to a variety of stimuli including tumor necrosis factor-alpha, granulocyte-macrophage colony stimulating factor, transforming growth factor-beta and the combination of lipopolysaccharide and phorbol myristate acetate. Interleukin-1 and interleukin-6 have been reported to influence the proliferation of cultured human fibroblasts. However, these cytokines had no significant effect on the proliferation of human keratinocytes or the SCC lines tested. Although it seems unlikely that interleukin-1 or interleukin-6 could directly influence keratinocyte proliferation in vivo, the capacity of these cells to synthesize and release these cytokines supports earlier observations that keratinocytes may play an important role in augmenting an immune or inflammatory response.
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PMID:Production of interleukin-1 and interleukin-6 by human keratinocytes and squamous cell carcinoma cell lines. 202 85

Adherence is an important initial step in the transition of a circulating monocyte to a tissue macrophage. This differentiation is accompanied by an augmented capacity to generate growth factors. We hypothesized that adherence itself might be an important trigger for a sequence of gene activation culminating in cells with increased mRNA encoding profibrotic growth factors such as platelet-derived growth factor B subunit (PDGF[B]) and transforming growth factor-beta (TGF-beta). After in vitro adherence, human monocytes had a biphasic increase in PDGF(B) mRNA with peaks at 6 h and 13 d. No increase in TGF-beta mRNA was observed. The 6-h increase in PDGF(B) mRNA was adherence dependent, and in addition, was abrogated when the cytoskeletal integrity was compromised by cytochalasin D. The 6-h increase in PDGF(B) mRNA was unaltered by adherence in the presence of the monocyte stimulus lipopolysaccharide. Adherence to either fibronectin or collagen-coated plastic had little consistent effect on PDGF(B) mRNA accumulation. The increased PDGF(B) mRNA observed in adherent monocytes was accompanied by increases in mRNAs of the early growth response genes c-fos (maximal at 20 min), c-jun, and EGR2 (maximal at 6-24 h). The increase in c-jun and EGR2, but not c-fos, mRNA was also abrogated by cytochalasin D. These observations suggest that adherence results in increases of c-fos, c-jun, EGR2, and PDGF(B) mRNA. In addition, the increases in c-jun, EGR2, and PDGF(B) may depend on cytoskeletal rearrangement. Modulation of these events at the time of adherence offers a mechanism by which differential priming of the cells may be accomplished.
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PMID:Adherence-dependent increase in human monocyte PDGF(B) mRNA is associated with increases in c-fos, c-jun, and EGR2 mRNA. 212 46

The multipotential cytokine, transforming growth factor-beta 2 (TGF-beta 2), is as effective as glucocorticoids in suppressing the production of tumor necrosis factor-alpha (TNF-alpha) by lipopolysaccharide (LPS)-stimulated macrophages, and this inhibition can be abrogated by exogenous interferon-gamma (IFN-gamma). Porcine alveolar macrophages triggered with LPS produce TNF-alpha as identified by complete blocking of cytotoxicity on WEHI 164 clone 13 cells in macrophage supernatants by a monoclonal antibody to human TNF-alpha. Platelet-derived porcine TGF-beta 2, at a concentration of 4 nM, inhibited LPS-induced production of TNF-alpha by 93%. Dexamethasone was as effective as TGF-beta 2, suppressing TNF-alpha production by 86% at a concentration of 4 nM. The natural but less potent glucocorticoid cortisol inhibited TNF-alpha production by 100% at a 100-fold higher concentration (400 nM). Recombinant PoIFN-gamma consistently primed LPS-triggered macrophages for increased production of TNF-alpha by 50-100%, and this priming was totally blocked by a polyclonal antibody to rPoIFN-gamma. Furthermore, the suppression in LPS-induced production of TNF-alpha caused by TGF-beta 2, dexamethasone, and cortisol could be reversed by addition of rPoIFN-gamma. These data show that alveolar macrophages can be effectively primed by rPoIFN-gamma even in the presence of moderately suppressive doses of TGF-beta 2 and antiinflammatory steroids.
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PMID:Role of interferon-gamma in counteracting the suppressive effects of transforming growth factor-beta 2 and glucocorticoids on the production of tumor necrosis factor-alpha. 212 84


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