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)

In response to viruses, monocytes and B cells produce TNF alpha. Therefore, we investigated TNF alpha gene expression and protein secretion in a human monocytic cell line, THP-1, and a Burkitt's lymphoma B-cell line, Namalwa, in response to hepatitis B virus (HBV). Stimulation by phorbol myristate acetate (PMA) (100 ng/ml for 48 h) induced TNF alpha secretion in THP-1 and Namalwa cells (100 to 300 pg/ml). In THP cells, the optimum response (> 2000 pg/ml) was obtained in the presence of a second mitogenic signal such as lipopolysaccharide (LPS) (10 microg/ml for 24 h). In our activation conditions, Northern blot analysis revealed a marked accumulation of TNF alpha mRNA species at 1.7 kb in both cell lines. When PMA- or PMA+LPS-stimulated THP-1 cells were exposed to HBV, TNF alpha protein and mRNA significantly decreased (> 50%). In contrast, HBV exposure of PMA-activated Namalwa cells resulted in strongly increased TNF alpha protein secretion (1 ng/ml). In this case, HBV induced TNF alpha mRNA accumulation that consisted of two types: a regular 1.7 kb and two novel high molecular weight (HMW) species at 3.7 and 4.3 kb. Exposure of stimulated THP-1 and Namalwa cells to HBV resulted in HBs and pre-S1 antigen production in the supernatants. In addition, HMW HBV DNA forms were detected in both cell lines, but with distinct HindIII restriction patterns. These findings indicate that TNF alpha gene expression may be differently regulated by HBV in activated human macrophages and B cells, and thus TNF alpha may be involved in the pathogenesis of HBV.
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PMID:Effect of hepatitis B virus on tumour necrosis factor (TNF alpha) gene expression in human THP-1 monocytic and Namalwa B-cell lines. 944 79

Reports on plasma concentrations of tumor necrosis factor alpha (TFN-alpha), interleukin 6 (IL-6), IL-10, and IFN-alpha in AIDS patients are contradictory. An alternative approach for the estimation of cytokine production is the measurement of lipopolysaccharide (LPS)-stimulated cytokine production in whole blood. We compared plasma concentrations of these cytokines, soluble TNF receptor (sTNFr) types I and II, and LPS-stimulated cytokine production in whole blood from clinically stable AIDS patients (n = 6) and healthy controls (n = 6). The plasma concentrations of TNF-alpha and sTNFr-II were higher in AIDS patients compared with controls (mean [95% CL]: TNF-alpha, 24 [17-31] and 8 [1-16] pg/ml, respectively, p < 0.01; sTNFr-II, 6.8 [4.6-9.0] and 3.2 [2.4-4.0] ng/ml, respectively, p < 0.01). The plasma concentrations of sTNFr-I and IL-10 were not different between AIDS patients and controls. Neither IL-6 nor IFN-alpha was detectable in any plasma sample. LPS-stimulated production in whole blood of TNF-alpha, IL-6, IL-10, and IFN-alpha was not different between AIDS patients and controls at any combination of LPS concentration (0, 0.1, 0.5, 1, 10, 100, and 1000 ng/ml) and duration of stimulation (0, 4, 8, and 24 hr). It is concluded that the plasma concentrations of TNF-alpha and sTNFr-II, but not of IL-6, IL-10, IFN-alpha, and sTNFr-I, are higher in AIDS patients compared with controls. The production of cytokines in LPS-stimulated whole blood does not provide information additional to the measurements of plasma concentrations.
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PMID:In vitro production of cytokines in whole blood versus plasma concentrations of cytokines in AIDS. 946 22

Tumor necrosis factor alpha (TNF alpha) is a key regulatory cytokine whose expression is controlled by a complex set of stimuli in a variety of cell types. Previously, we found that the monocyte/macrophage-enriched nuclear transcription factor C/EBPbeta played an important role in the regulation of the TNF alpha gene in myelomonocytic cells. Abundant evidence suggests that other transcription factors participate as well. Here we have analyzed interactions between C/EBPbeta and c-Jun, a component of the ubiquitously expressed AP-1 complex. In phorbol myristate acetate (PMA)-treated Jurkat T cells, which did not possess endogenous C/EBPbeta, expression of c-Jun by itself had relatively little effect on TNF alpha promoter activity. However, the combination of C/EBPbeta and c-Jun was synergistic, resulting in greater than 130-fold activation. This effect required both the leucine zipper and DNA binding domains, but not the transactivation domain, of c-Jun, plus the AP-1 binding site centered 102/103 bp upstream of the transcription start site in the TNF alpha promoter. To determine if C/EBPbeta and c-Jun might cooperate to regulate the cellular TNF alpha gene in myelomonocytic cells, U937 cells that possess endogenous C/EBPbeta and were stably transfected with either wild-type c-Jun or the transactivation domain deletion mutant (TAM-67) were examined. U937 cells expressing ectopic wild-type c-Jun or TAM-67 secreted over threefold more TNF alpha than the control line in response to PMA plus lipopolysaccharide. Transient transfection of the U937 cells expressing TAM-67 suggested that TAM-67 binding to the -106/-99-bp AP-1 binding site cooperated with endogenous C/EBPbeta in the activation of the -120 TNF alpha promoter-reporter. DNA binding assays using oligonucleotides derived from the TNF alpha promoter suggested that C/EBPbeta and c-Jun interact in vitro and that the interaction may be DNA dependent. Our data demonstrate that the TNF alpha gene is regulated by the interaction of the ubiquitous AP-1 complex protein c-Jun and the monocyte/macrophage-enriched transcription factor C/EBPbeta and that this interaction contributes to the expression of the cellular TNF alpha gene in myelomonocytic cells. This interaction was unique in that it did not require the c-Jun transactivation domain, providing new insight into the cell-type-specific regulation of the TNF alpha gene.
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PMID:Tumor necrosis factor alpha gene regulation: enhancement of C/EBPbeta-induced activation by c-Jun. 956

Lymphotoxin (LT)alpha knockout mice, as well as double LTalpha/tumor necrosis factor (TNF) knockout mice, show a severe splenic disorganization with nonsegregating T/B cell zones and complete absence of primary B cell follicles, follicular dendritic cell (FDC) networks, and germinal centers. In contrast, as shown previously and confirmed in this study, LTbeta-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks. We show here that similar to the splenic phenotype of LTbeta-deficient mice, complementation of LTalpha knockout mice with TNF-expressing transgenes leads to a p55 TNF receptor-dependent restoration of B/T cell zone segregation and a partial preservation of primary B cell follicles, FDC networks, and germinal centers. Notably, upon lipopolysaccharide challenge, LTalpha knockout mice fail to produce physiological levels of TNF both in peritoneal macrophage supernatants and in their serum, indicating a coinciding deficiency in TNF expression. These findings suggest that defective TNF expression contributes to the complex phenotype of the LTalpha knockout mice, and uncover a predominant role for TNF and its p55 TNF receptor in supporting, even in the absence of LTalpha, the development and maintenance of splenic B cell follicles, FDC networks, and germinal centers.
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PMID:Complementation of lymphotoxin alpha knockout mice with tumor necrosis factor-expressing transgenes rectifies defective splenic structure and function. 970 56

Many pathogenic Escherichia coli produce the toxin alpha-hemolysin (Hly), and lipopolysaccharide (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) have all been recognized as important effector molecules during infections by gram-negative organisms. Despite the characterization of many in vitro effects of hemolysin, no direct relationship has been established between hemolysin, LPS, proinflammatory cytokine production, and E. coli-induced mortality. Previously, we have shown in vivo that hemolysin elicits a distinct IL-1alpha spike by 4 h into a lethal hemolytic E. coli infection. Using three transformed E. coli strains, WAF108, WAF270, and WAH540 (which produce no Hly [Hlynull], acylated Hly [Hlyactive], or nonacylated Hly [Hlyinactive], respectively), we sought to determine the specific roles of hemolysin acylation, LPS, IL-1, and TNF in mediating the lethality of E. coli infection in mice. WAF270 was 100% lethal in BALB/c, C3H/HeJ, and C57BL/6 mice; in mice pretreated with antibody to the type 1 IL-1 receptor; in type 1 IL-1 receptor-deficient mice; and in dual (type 1 IL-1 receptor-type 1 TNF receptor)-deficient mice at doses which were nonlethal (0%) with both WAF108 and WAH540. At lethal doses, WAF270 killed by 6 +/- 2.3 h while WAF108 and WAH540 killed at 36 +/- 9.4 and 36 +/- 13.8 h, respectively. These differences in mortality were not due to IL-1 or TNF release, and the enhanced expression of LPS, which corresponded to Hly expression, was not likely the primary factor causing mortality. We demonstrate that bacterial fatty acid acylation of hemolysin is required in order for it to elicit IL-1 release by monocytes and to confer its virulence on E. coli.
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PMID:Hemolytically active (acylated) alpha-hemolysin elicits interleukin-1beta (IL-1beta) but augments the lethality of Escherichia coli by an IL-1- and tumor necrosis factor-independent mechanism. 971 70

Bacterial endotoxin, lipopolysaccharide (LPS), is a causative agent of Gram-negative septic shock. However, if preadministered at a low dose, LPS makes mice resistant to subsequent endotoxin challenge, the phenomenon known as LPS tolerance. Here we demonstrated that the pharmaceutical preparation of Gram-positive Streptococcus pyogenes, OK-432, also induced a state analogous to LPS tolerance if administered 6-48 h prior to LPS challenge. The preadministration of OK-432 increased the lethal dose of LPS threefold in BDF1 mice, and this was accompanied by reduced gene expression of IL-6, IFN-gamma, inducible nitric oxide synthase, and IL-10 in spleen and peritoneal cells. Serum concentrations of IL-6 and IFN-gamma were also suppressed by the preadministration of OK-432. In contrast to the LPS tolerance, the levels of TNF-alpha mRNA were not suppressed in OK-432-administered mice, and their peritoneal cells produced high levels of TNF-alpha and soluble TNF receptor p75 in response to LPS in vitro. Peritoneal cells from OK-432 but not LPS-administered mice were hyporesponsive to IFN-gamma in terms of nitric oxide synthesis, and this hyporesponsiveness to IFN-gamma was abrogated by anti-IL-10 antibodies. Likewise, peritoneal cells from both OK-432- and LPS-administered mice were hyporesponsive to LPS, serum, TNF-alpha, IFN-gamma, and PMA in terms of IL-6 production. Anti-IL-10 antibodies increased IL-6 production eightfold in cells from OK-432-administered mice, but marginally in cells from LPS-administered mice. Even in peritoneal cells from OK-432-administered mice, anti-IL-10 antibodies failed to fully restore IL-6 production. Thus, the hyporesponsive state of peritoneal cells was mediated by both IL-10-dependent and -independent mechanisms. These results demonstrated that OK-432 controlled endotoxin shock by blocking the cytokine cascade from TNF-alpha.
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PMID:Control of endotoxin shock by the dried preparation of low virulent Streptococcus pyogenes OK-432. 975 39

Vascular endothelial cells (EC) are primary cellular targets for the actions of pro-inflammatory cytokines such as tumor necrosis factor (TNF). We have studied the signaling pathways used by TNF that lead to new gene expression (endothelial cell activation) or apoptosis (endothelial cell injury). Both responses are initiated by ligand binding to TNFR-I (the p55 receptor). TNF initiates transcription of the E-selectin gene by activation of the transcription factors NF-kappa B and c-Jun/ATF-2. NF-kappa B is activated following degradation of I kappa B alpha and I kappa B-beta. Activation of c-Jun/ATF-2 involves new c-Jun synthesis, and more importantly, phosphorylation of the amino terminus of c-Jun by Jun N-terminal kinase (JNK). Studies in transiently transfected human umbilical vein endothelial cells have revealed that NF-kappa B activation is initiated through the adaptor protein TRAF-2. The activation of JNK also depends upon TRAF-2 and probably involves a kinase cascade initiated by the small G proteins Rac-1 and/or cdc-42. Normally, TNF does not injure human EC. However, TNF can cause apoptosis of EC when cells are co-treated with either the protein synthesis inhibitor cycloheximide (CHX) or the lipid mediator ceramide (cer). The pathways leading to apoptosis following treatment with TNF + CHX and TNF + cer are different since only TNF + CHX is blocked by the caspase inhibitors crmA protein or the peptide zVAD.fmk while only TNF + cer is blocked by the anti apoptotic proteins Bcl-2, Bcl-XL or Al. Both pathways may be inhibited by the anti-apoptotic protein A-20. TNF does not cause the liberation of cer in EC, perhaps because of limited expression of neutral sphingomyelinase-activating adaptor protein FAN. These observations suggest that TNF normally acts as an activator of EC but may change from an activator to a killer of EC when combined with agents that release ceramide, such as u.v. irradiation or cytotoxic drugs, or with ceramide mimetics such as lipopolysaccharide. The activation and injury of endothelial cells induced by TNF and other proinflammatory cytokines may underlie the local effects of these mediators in vivo.
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PMID:Activation and injury of endothelial cells by cytokines. 976 10

Estrogen replacement therapy (ERT) is known to prevent bone loss following the menopause, but the mechanism for this is unclear. Estrogen may suppress the secretion of certain bone-resorbing cytokines. The aim of this study was to assess the effect of ERT on the levels of cytokines measured in peripheral blood. We measured cytokines in 10 postmenopausal women (ages 56-59, 3-9 years since menopause) treated with ERT and 10 age-matched (54-59 years, 4-10 years since menopause) untreated women as controls. Samples of blood were taken and used for mononuclear cell cultures, whole blood (WB) cultures, and the separation of serum. The cultures were treated with lipopolysaccharide (LPS; 500 ng/ml) and hydrocortisone (10(-6) M). The conditioned medium from cultures and the serum were then assayed for interleukin-6 (IL-6), IL-1alpha IL-1beta, IL-1 IL-1ra, tumor necrosis factor alpha (TNF-alpha), and granulocyte macrophage colony stimulating factor (GM-CSF) by enzyme-linked immunosorbent assay. M-CSF and the soluble cytokine receptors soluble IL-6 receptor (sIL-6r) and soluble TNF receptor type 1 (sTNFr1) were also measured in serum and M-CSF in stimulated WB cultures. Measurements were corrected for mononuclear cell count. We also measured serum bone-specific alkaline phosphatase (ibAP) in all subjects. We found that LPS stimulated secretion of all cytokines both in WB and isolated cell cultures, and that this was attenuated by hydrocortisone. A significantly higher ratio of IL-1beta/IL-1ra (p = 0.02) in LPS stimulated WB cultures was seen in the untreated women. Levels of IL-1beta and IL-1alpha measured in WB cultures were lower and IL-1ra was higher in the ERT-treated group but these results were not significant. BAP was higher in the untreated group (p = 0.005) and correlated with IL-alpha/IL-1ra in the whole group (r = 0.49, p = 0.03). Results of other measurements showed no significant differences between groups. We conclude that estrogen may prevent bone loss following the menopause by altering the balance between IL-1beta and IL-1ra.
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PMID:Effects of estrogen therapy of postmenopausal women on cytokines measured in peripheral blood. 978 46

Signaling through tumor necrosis factor receptor type 1 (TNFR-1) using a pathway that involves nuclear factor kappaB (NF-kappaB), interleukin-6 (IL-6), and STAT3 is required for the initiation of liver regeneration. We have proposed that TNF primes hepatocytes to respond to the mitogenic effect of growth factors, but so far, there has been no experimental demonstration that TNF enhances growth factor responses of hepatocytes. To test this hypothesis, we infused hepatocyte growth factor (HGF) and transforming growth factor (TGF-) (40 microgram/24 h) directly into the portal vein of rats for 24 hours using osmotic pumps and determined whether TNF injection (5 microgram per rat) would significantly increase hepatocyte DNA labeling in these animals. All rats received 5-bromo-2'-deoxyuridine (BrdU) by intraperitoneal delivery during a 48-hour period (i.e., BrdU infusion continued for 24 hours after the end of growth factor administration). BrdU labeling in the liver was measured by both immunohistochemistry and flow cytometry, and the results obtained by these methods showed excellent concordance. The results demonstrate that TNF transiently activates NF-kappaB and STAT3 and increases the proliferative response of hepatocytes to HGF or TGF- by fourfold. Priming effects on hepatocyte DNA replication were also obtained with injection of lipopolysaccharide (LPS) and gadolinium chloride (GdCl3), agents that release TNF in the liver. Similarly to TNF, GdCl3 injection caused the activation of NF-kappaB and STAT3, reaching a maximum 8 to 12 hours after the injection. The results show that TNF acts as a primer to sensitize hepatocytes to the proliferative effects of growth factors and offers a mechanism to explain the initiation and progression phases of liver regeneration after partial hepatectomy (PH).
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PMID:Tumor necrosis factor primes hepatocytes for DNA replication in the rat. 979 5

The pulmonary host response to infection and inflammation appears, at least in part, to be compartmentalized from the systemic host response. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in lung inflammation and injury, but its site(s) of action has not been clearly defined. To investigate this, transgenic mice (surfactant apoprotein C promotor/soluble TNF receptor type II-Fc fusion protein ([SPCTNFRIIFc] mice) were generated in which TNF-alpha was selectively antagonized in the distal lung through tissue-specific expression of sTNFRIIFc, a soluble TNF inhibitor. The lung inflammatory response in these mice to pulmonary challenge with Micropolyspora faeni antigen or lipopolysaccharide (LPS) was compared with the response of wild-type mice, wild-type mice treated with recombinant sTNFRIIFc intravenously, and type I TNF-receptor knockout mice. Recruitment of polymorphonuclear leukocytes (PMN) to the lung after challenge with M. faeni antigen was essentially abolished in the TNFRI knockout mice and markedly reduced in the SPCTNFRIIFc mice. Wild-type mice given sTNFRIIFc intravenously in amounts resulting in lung concentrations similar to those in SPCTNFRIIFc mice also showed significantly reduced lung PMN recruitment, whereas those given doses that achieved such concentrations in the blood but low levels in the lung did not. In contrast, PMN recruitment to the lung following aerosol challenge with LPS was reduced significantly in the TNFRI knockout mice and in mice given high-dose sTNFRIIFc intravenously, but was not reduced significantly in SPCTNFRIIFc mice. Thus, inhibition of PMN recruitment in response to M. faeni antigen correlated largely with the extent of intrapulmonary inhibition of TNF-alpha, whereas the response to LPS correlated best with the extent of extrapulmonary inhibition of TNF-alpha. These studies indicate that TNF-alpha may act at different loci to mediate lung inflammation, with the site of action depending in part on the nature of the inflammatory stimulus, and that SPCTNFRIIFc mice provide a tool by which the locus of TNF action can be addressed.
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PMID:The locus of tumor necrosis factor-alpha action in lung inflammation. 984 22


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