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

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator in sepsis and septic shock. Kupffer cells (KCs) are the resident macrophages of the liver and are potent producers of TNF-alpha in response to inflammatory stimuli such as bacterial endotoxin or lipopolysaccharide (LPS). Although the effects of exogenous cytokines such as interferon-gamma on TNF-alpha production by macrophages have been fairly well studied, the intracellular pathways regulating KC TNF-alpha synthesis are largely unknown. We investigated the role of guanylate cyclase and cGMP in LPS-induced KC TNF-alpha synthesis. Exogenous 8-BrcGMP and dbcGMP increased LPS-stimulated TNF-alpha synthesis but had no effect on KC TNF-alpha in the absence of LPS. Sodium nitroprusside (SNP), a nitric oxide-releasing substance that stimulates guanylate cyclase, increased TNF-alpha synthesis in response to LPS, whereas methylene blue and LY83583, guanylate cyclase inhibitors, decreased KC TNF-alpha synthesis. The inhibitory effect of methylene blue could be overcome with exogenous dbcGMP or SNP. Our results demonstrate that guanylate cyclase and cGMP mediate LPS-induced KC TNF-alpha synthesis and suggest that agents that alter cyclic nucleotide metabolism in KCs may affect the response of these cells to inflammation and inflammatory stimuli.
 ...
PMID:Cyclic GMP and guanylate cyclase mediate lipopolysaccharide-induced Kupffer cell tumor necrosis factor-alpha synthesis. 785 45

Tumor necrosis factor-alpha is a principal mediator of the pathophysiological effects of endotoxemia and endotoxin shock. Tumor necrosis factor-alpha also contributes to the stimulation of nitric oxide synthesis by the induction of the enzyme nitric oxide synthase in a variety of tissues. Although the importance of tumor necrosis factor-alpha in the induction of nitric oxide synthase activity in vitro is well known, its role in in vivo nitric oxide synthesis has not been convincingly established. We were interested in determining whether tumor necrosis factor-alpha plays a significant role in the in vivo induction of nitric oxide synthesis. In Corynebacterium parvum-primed mice, lipopolysaccharide injection resulted in elevated serum tumor necrosis factor-alpha levels early and increased hepatic enzyme release (641 +/- 80 IU AST/L; 22.7 +/- 1.9 IU ornithine carbamoyltransferase per liter) and plasma nitrite and nitrate (804 +/- 84 mumol/L) 5 hr after lipopolysaccharide injection. Polyclonal rabbit anti-mouse anti-tumor necrosis factor-alpha reduced in vivo tumor necrosis factor-alpha levels (1 hr, 7,332 +/- 1,492 U tumor necrosis factor-alpha per milliliter) and reduced nitric oxide synthesis as measured by plasma nitrite and nitrate (352 +/- 69 mumol/L). Polyclonal rabbit anti-mouse anti-tumor necrosis factor-alpha also reduced lipopolysaccharide-induced hepatic enzyme release (428 +/- 33 IU AST/L; 16.0 +/- 2.5 IU ornithine carbamoyltransferase per liter). NG-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthesis, also decreased plasma nitrite and nitrate (104 +/- 9 mumol/L) but increased the lipopolysaccharide-induced hepatic injury (797 +/- 66 IU AST/L; 33.1 +/- 2.1 IU ornithine carbamoyltransferase per liter).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Tumor necrosis factor-alpha regulates in vivo nitric oxide synthesis and induces liver injury during endotoxemia. 792 8

Kupffer cells are known to produce tumor necrosis factor-alpha upon stimulation with endotoxin or viruses. This tumor necrosis factor-alpha synthesis is suppressed by prostaglandin E2 or dexamethasone. Using Northern blotting and reverse transcriptase-polymerase chain reaction, it is demonstrated that endotoxin-induced tumor necrosis factor-alpha synthesis is blocked by prostaglandin E2 or dibutyryl 3':5'-cyclic adenosine monophosphate on the transcriptional level. Tumor necrosis factor-alpha itself suppressed endotoxin-evoked tumor necrosis factor-alpha mRNA expression when given in a narrow time interval with lipopolysaccharide. Interleukin-10 of human or mouse origin also inhibited the synthesis of tumor necrosis factor-alpha mRNA and protein when given more than 2 h prior to the endotoxin challenge. The suppressive effect of prostaglandin E2 lasted for more than 36 h while IL-10 blocked tumor necrosis factor-alpha production for barely 24 h. Dexamethasone reduced the endotoxin-induced tumor necrosis factor-alpha mRNA formation by approximately 50% only, although it led to nearly complete inhibition of the synthesis of the mature protein. Taken together with reverse transcriptase-polymerase chain reaction data revealing significant amounts of tumor necrosis factor-alpha mRNA in resting Kupffer cells, an additional posttranscriptional regulation of tumor necrosis factor-alpha synthesis has to be assumed. Tumor necrosis factor-alpha mRNA was not induced by interferon-gamma, interleukin-1 beta or interleukin-6 (the latter two cytokines are also synthesized by Kupffer cells), but a 24-h prestimulation of liver macrophages with interferon-gamma or phorbol ester had a modest priming effect.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Regulation of the mRNA expression for tumor necrosis factor-alpha in rat liver macrophages. 793 Apr 83

Many studies have shown that alcohol consumption is associated with alteration in immune responses and increased incidence of infection in the host. Tumor necrosis factor (TNF) is a potent soluble mediator of immunoregulation and inflammation, and plays a very important role in host's defenses against infection and tumor. We propose that one of the mechanisms of alcohol-mediated immunosuppression may be due to a defect in the synthesis and release of the TNF. To determine this, we studied the direct effect of alcohol on lipopolysaccharide (LPS)-induced TNF production by whole blood and total mononuclear cell from normal subjects. Aliquots of blood samples (1 ml) or ficoll-hypaque separated total mononuclear cells (1 x 10(6)/ml) were cultured with different concentrations of either ethanol or acetaldehyde in the presence or absence of LPS for 4 hr at 37 degrees C. Plasma samples and culture supernatants were assayed for TNF levels in a bioassay using a TNF-sensitive WEHI 164 subclone 13 cell line. LPS at 10 micrograms/ml produced a maximal level of TNF compared with lower (1 micrograms/ml) or higher concentration (50 micrograms/ml) of LPS. Kinetics studies showed that an incubation time of 4 hr with LPS produced a maximum level of TNF production by blood. Alcohol, as low as 0.1% concentration, produced significant suppression of LPS-induced TNF production by whole blood, whereas alcohol at 0.2 and 0.3% concentrations were required to produce a significant suppression of TNF production by separated mononuclear cells. Anti-TNF-alpha antibodies significantly neutralized the LPS-induced TNF that suggests that blood monocytes may be the primary source of TNF production.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Suppression of tumor necrosis factor production by alcohol in lipopolysaccharide-stimulated culture. 794 62

Endotoxin (lipopolysaccharide [LPS]) stimulates the production of cytokines, which mediate many of the metabolic effects associated with infection. In LPS-sensitive C57B1/6 mice, LPS doses as low as 0.01 micrograms per mouse decreased adipose tissue lipoprotein lipase (LPL) activity by greater than 50%. In LPS-resistant C3H/HeJ mice, which do not produce cytokines in response to LPS, doses of LPS as high as 10 micrograms per mouse did not affect LPL activity in adipose tissue. In muscle of C57Bl/6 mice, LPL activity was decreased by 27% after 10 micrograms of LPS, whereas in C3H/HeJ mice there was no effect. These results indicate that the LPS-induced decrease in both adipose and muscle LPL activity is mediated by cytokines. Tumor necrosis factor (TNF), interleukin (IL)-1, leukemia-inhibiting factor (LIF), interferon alfa, and interferon gamma all decreased adipose tissue LPL activity in intact mice. In skeletal and cardiac muscle, only IL-1 and interferon gamma decreased LPL activity, whereas TNF, LIF, and interferon alfa had no effect. Inhibition of TNF activity blocked the increase in serum triglycerides that is characteristically observed after LPS but did not affect the ability of LPS to decrease adipose tissue LPL activity. Inhibition of IL-1 activity with IL-1 receptor antagonist partially inhibited the increase in serum triglycerides; however, the ability of LPS to decrease LPL activity in either adipose or muscle tissue was not affected. These data indicate that although TNF and IL-1 play a role in mediating the increase in serum triglyceride levels, these cytokines do not play a crucial role in the inhibition of either adipose or muscle LPL activity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of endotoxin and cytokines on lipoprotein lipase activity in mice. 794 14

The pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are acute-phase proteins produced by liver epithelial cells. PTX3 was recently cloned as an interleukin-1 (IL-1)-inducible gene in endothelial cells, with structural similarities to pentraxins in the C-terminal half of the molecule. The present study was designed to investigate the expression of PTX3 in the human leukocyte populations. Human peripheral blood mononuclear cells exposed to lipopolysaccharide (LPS) or IL-1 beta expressed significant levels of PTX3 mRNA. Tumor necrosis factor-alpha (TNF-alpha) was a less-effective inducer of PTX3, whereas IL-6, monocyte chemotactic protein-1, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interferon-gamma were inactive. Among leukocytes, only monocytes exposed to inflammatory cytokines or LPS expressed the PTX3 transcript, which was undetectable in resting or stimulated polymorphonuclear cells, T or B lymphocytes, and natural killer cells. PTX3 mRNA was also inducible in in vitro monocyte-derived macrophages, in tumor-associated macrophages, and in the myelomonocytic cell lines HL60, U937, and THP1, but not in GFD8, with the latter possibly representative of earlier stages of myelomonocytic differentiation. T- and B-cell lines had no detectable PTX3. Inhibition of transcription by actinomycin D blocked induction of PTX3 in monocytes and nuclear run-on analysis showed that LPS induces the expression of the PTX3 gene at the transcriptional level in isolated monocytes. Cycloheximide had no effect on PTX3 induction in U937 cells, but was inhibitory on monocytes exposed to LPS or IL-1 beta. Monoclonal antibody against TNF and the IL-1 receptor antagonists did not inhibit induction of PTX3 in monocytes by LPS, thus excluding these cytokines as secondary stimulators of PTX3. IL-4, but not dexamethasone or transforming growth factor-beta, inhibited PTX3 expression in monocytes. Using a PTX3-specific antiserum, release of PTX3 protein was demonstrated for the first time in stimulated monocytes as well as in endothelial and fibroblastic cells. Thus, PTX3, unlike the classical pentraxins CRP and SAP, is expressed and released by cells of the monocyte-macrophage lineage exposed to inflammatory signals.
 ...
PMID:Inducible expression of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes. 794 2

Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine involved in the immunopathologic consequences of allograft rejection. We have previously demonstrated that anti-TNF antibody treatment prolongs cardiac allograft survival in rats. To elucidate the mechanism of anti-TNF antibody in modulating the immune response, we investigated TNF production by spleen and lymph node cells from anti-TNF antibody-treated Lewis rats who received MHC-mismatched Brown Norway rat cardiac allografts. In 10 untreated rats, cardiac allografts were rejected at 6.8 +/- 0.6 days after transplantation (mean +/- SD). Anti-TNF antibody treatment enhanced graft survival to 12.7 +/- 1.4 days (P < 0.001 vs controls). In other anti-TNF antibody-treated recipients spleen and lymph node cells were isolated on Day 5 after transplant. TNF production was measured and showed significantly less TNF than those from untreated (no anti-TNF antibody), transplanted recipient rats (28.7 u/10(6) spleen cells vs 76.4 u/10(6) spleen cells at 2 hr and 4.6 u/10(6) lymph node cells vs 9.2 u/10(6) lymph node cells at 24 hr). Furthermore, following lipopolysaccharide stimulation, spleen cells from anti-TNF-treated rats again produced significantly less TNF than those from untreated transplanted rats (68.9 u/10(6) cells vs 189.4 u/10(6) cells at 2 hr). Finally, with allogeneic cell stimulation, anti-TNF treated rats again produced significantly less TNF than untreated transplanted rats (spleen cells, 2.2 u/10(6) cells vs 40.4 u/10(6) cells at 24 hr; lymph node cells, 1.2 u/10(6) cells vs 22.2 u/10(6) cells at 72 hr). These findings suggest that anti-TNF antibody treatment may not only neutralize TNF activity, but also suppress TNF production itself, providing a new insight into the regulation of TNF by anti-TNF antibody.
 ...
PMID:Inhibition of tumor necrosis factor production by lymphocytes from anti-TNF antibody-treated, cardiac-allografted rats. 801 17

Tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1) affect epithelial cell ion transport. However, the site of action along the nephron has not been elucidated fully for these cytokines. Thus, the effect of TNF and IL-1 on the ion transport function of primary cultured medullary thick ascending limb of Henle's loop (mTALH) cells was determined by measuring rubidium (86Rb) uptake. TNF, IL-1, and lipopolysaccharide (LPS), a known activator of cytokine production, inhibited 86Rb uptake by cultured mTALH cells after a 24-h incubation period but had no effect when incubated with the cells for 1 or 4 h. Furthermore, mTALH cells produced biologically active TNF after stimulation with LPS for 24 h, and the LPS-induced inhibition of 86Rb uptake was abolished in the presence of an anti-TNF antibody, suggesting that TNF produced by the mTALH cells acted in an autocrine manner to inhibit 86Rb uptake. The effects of LPS on 86Rb uptake also were inhibited by the cyclooxygenase inhibitor, indomethacin. As TNF increased prostaglandin E2 synthesis by cultured mTALH cells and as prostaglandin E2 also inhibited 86Rb uptake, LPS presumably inhibited 86Rb uptake by inducing a TNF-mediated increase in prostaglandin synthesis. These data demonstrate that a prostanoid produced by mTALH cells mediates the inhibitory effect of LPS and TNF on 86Rb uptake and imply that endogenous TNF inhibits ion fluxes in the mTALH via a prostaglandin-dependent mechanism.
 ...
PMID:Cytokines affect ion transport in primary cultured thick ascending limb of Henle's loop cells. 802 89

Tumor necrosis factor (TNF) of hepatic origin is thought to play a pivotal role early in the genesis of the septic shock syndrome, regardless of microbial etiology. To determine if production of TNF by Kupffer cells varies with microbial taxonomic class, we measured TNF secretory responses in primary cultures of rat Kupffer cells to numerically equivalent gram-negative bacterial or fungal phagocytic challenges. After a 30-min exposure to media, latex beads, soluble Escherichia coli lipopolysaccharide (LPS; serotype 055:B5), live or Formalin-fixed E. coli (serotype 055:B5), live or Formalin-fixed yeast-phase Candida albicans, or live hyphal-phase Candida, samples of culture supernatant were assessed at 30, 60, 120, and 240 min and at 24 h for TNF bioactivity by L929 cell cytotoxicity. Compared with media and latex bead controls, TNF levels progressively increased for up to 240 min after either LPS and equivalently in live E. coli or Formalin-fixed E. coli groups (P < 0.05). Formalin-fixed yeast-phase and live extracellular hyphal-phase C. albicans failed to stimulate production of TNF at any time point (6.9 +/- 0.7 and 8.7 +/- 0.4 U/ml, respectively, at t = 240 min; P < 0.05 vs. E. coli). In contrast, internalization of live yeast-phase C. albicans with subsequent hyphal formation and growth within Kupffer cells was accompanied by a rise in supernatant TNF levels (14.5 +/- 1.8 U/ml at t = 240 min).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Differential production of TNF by Kupffer cells after phagocytosis of E. coli and C. albicans. 807 22

Secretion of unique eosinophil granule constituents may play a role in allergic and parasitic reactions. Therefore we have investigated possible mechanisms for regulation of secretion in eosinophils. A hemolytic plaque assay and an enzyme-linked immunospot (ELISPOT) assay were developed for detection of secreted eosinophil cationic protein (ECP) from single adherent eosinophils. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA) induced release of ECP in a dose-dependent fashion but 4-alpha-PMA, an analogue that does not activate protein kinase C, did not cause degranulation. Staurosporine and K252a, inhibitors of protein kinase C, decreased PMA-induced ECP secretion. Low concentrations of cytochalasin B enhanced PMA-induced secretion but high concentrations had an inhibitory effect. The calcium ionophores A23187 and ionomycin were weaker secretagogues than PMA. Tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, interleukin-5, N-formylmethionyl-leucyl-phenylalanine, and lipopolysaccharide caused little or no degranulation in adherent eosinophils. Preincubation of eosinophils with antibodies to CD18, the common beta chain of leukocyte adhesion proteins, resulted in inhibition of PMA-induced ECP release from adherent cells. 1,2-Bis(O-aminophenyl)-ethane-ethane-N,N,N',N'-tetraacetic acid (BAPTA), an agent that acts intracellularly by chelation of calcium, also inhibited PMA-mediated ECP release. In conclusion, PMA induces release of ECP from single adherent eosinophils and the effect appears to be mediated via protein kinase C and, in contrast to that in neutrophils, to be dependent on CD11/CD18 leukocyte integrins.
 ...
PMID:Phorbol ester-induced degranulation in adherent human eosinophil granulocytes is dependent on CD11/CD18 leukocyte integrins. 809 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>