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)

Tumour necrosis factor (TNF), jointly referring to TNF alpha and TNF beta, is a central mediator of immune and inflammatory responses; its activities are mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75) (reviewed in refs 1-3). The cytoplasmic domains of the TNFRs are unrelated, suggesting that they link to different intracellular signalling pathways. Although most TNF responses have been assigned to one or the other of the TNF receptors (mostly TNFR1), there is no generally accepted model for the physiological role of the two receptor types. To investigate the role of TNFR1 in beneficial and detrimental activities of TNF, we generated TNFR1-deficient mice by gene targeting. We report here that mice homozygous for a disrupted Tnfr1 allele (Tnfr1(0)) are resistant to the lethal effect of low doses of lipopolysaccharide after sensitization with D-galactosamine, but remain sensitive to high doses of lipopolysaccharide. The increased susceptibility of Tnfr1(0)/Tnfr1(0) mutant mice to infection with the facultative intracellular bacterium Listeria monocytogenes indicates an essential role of TNF in nonspecific immunity.
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PMID:Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. 839 24

In patients with common variable immunodeficiency (CVI), we have previously defined a subgroup of patients (CVIHyper) characterized by decreased numbers of CD4+ lymphocytes in peripheral blood, splenomegaly, and persistent immune activation in vivo, particularly of monocytes/macrophages. To further characterize this hyperactivity, parameters of activation of the tumor necrosis factor (TNF) system (TNF alpha and soluble TNF receptors [sTNFRs]) were measured in 24 patients with CVI and 20 healthy controls. Patients with CVI had significantly higher serum levels of TNF alpha and both types of sTNFRs, with the highest levels in the CVIHyper subgroup. In vitro, peripheral blood mononuclear cells (PBMC) and purified monocytes from CVIHyper patients spontaneously released significantly higher levels, and, after lipopolysaccharide (LPS) stimulation, significantly lower levels of TNF alpha and soluble p75-TNFR than cells from both other CVI patients and healthy controls. CVIHyper patients also had significantly higher TNF alpha:sTNFRs ratios in both serum and in unstimulated PMBC supernatants. The present study demonstrates persistent in vivo activation of the TNF system in CVI, particularly in the CVIHyper subgroup. This activation may contribute to the pathogenesis of both clinical and immunologic manifestations in CVI.
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PMID:Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency--possible immunologic and clinical consequences. 855 90

It has been shown that lead (Pb) potentiates lipopolysaccharide (LPS) lethality in animals by increasing the secretion and uptake or reactivity of tumor necrosis factor-alpha (TNF-alpha). Herein we report that PbCl2 increased TNF-alpha secretion from LPS-treated human peripheral blood mononuclear cells (PBMC) in a concentration- and time-dependent manner. PbCl2 also increased total cellular TNF-alpha levels but had no effect on the steady-state levels of TNF-alpha mRNA. PbCl2 decreased membrane-associated TNF-alpha (mTNF-alpha) on LPS-treated monocytes, whereas PbCl2 increased TNF-alpha receptor (TNF-R) p55 surface expression, and had no effect on TNF-R p75 surface expression by LPS-treated monocytes. Overall, the results suggest that PbCl2 increases TNF-alpha expression by posttranscriptional mechanisms in human PBMC, and enhances the reactivity and uptake of TNF-alpha by increasing the surface expression of TNF-R p55.
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PMID:The heavy metal lead modulates the expression of both TNF-alpha and TNF-alpha receptors in lipopolysaccharide-activated human peripheral blood mononuclear cells. 869 Oct 80

The immunomodulating capacity of the methylxanthine A802715 (5-hydroxy-5-methyl)hexyl-3-methyl-7-propylxanthin) was investigated in various murine models of endotoxemia and compared with that of the chemically related reference compound pentoxifylline. At a dose of 180 mg/kg both compounds protected mice against a lethal shock dose of lipopolysaccharide (LPS) (5 mg/kg) in nonsensitized mice and against LPS (5 micrograms/kg)-initiated liver failure in D-galactosamine (700 mg/kg)-sensitized animals. The methylxanthines attenuated systemic release of endogenous tumor necrosis factor (TNF) and interferon-gamma during endotoxic shock, and potently up-regulated early production of circulating interleukin-10 and interleukin-6. Treatment of mice with A802715 alone induced levels of circulating soluble TNF receptors (sTNF-R p55 and p75) 3- to 4-fold higher than those of controls. This increase was additive to the one elicited by LPS. Moreover, pentoxifylline and A802715 prevented liver injury due to intravenous injection of recombinant TNF in D-galactosamine-sensitized mice. In primary cultures of murine hepatocytes, A802715 (500 microM) as well as other cAMP-raising compounds conferred protection from TNF cytotoxicity. We concluded that, in addition to a direct target cell protection via an increase in intracellular cAMP, methylxanthines prevented the systemic toxicity of LPS in mice by a further principle, i.e., by a shift of the humoral response to LPS in favor of an enhanced release of immunosuppressive cytokines.
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PMID:Enhanced release of interleukin-10 and soluble tumor necrosis factor receptors as novel principles of methylxanthine action in murine models of endotoxic shock. 876 78

Tumor necrosis factor (TNF) is a central mediator of immune and inflammatory responses. Its activities have been shown to be mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75). The cytoplasmic domains of both TNF receptors are unrelated, suggesting that they link to different intracellular signaling pathways. To determine their role in vivo in lipopolysaccharide (LPS)- and TNF-induced skin inflammatory necrosis, TNFR1-, TNFR2-, and TNF lymphotoxin-alpha (LT alpha)-deficient mice were used. Skin abscesses were experimentally induced with local application of TNF or LPS. Large macroscopic ulcerations were observed in TNF-injected wild-type animals and to a slightly lesser extent in TNFR2-deficient mice with tissue destruction in both cases extending deep into the dermis. Tissue destruction was accompanied by an intense immune infiltrate composed mainly of neutrophils, lymphocytes, and macrophages. TNFR1-deficient and TNFR1/TNFR2-double-deficient mice, however, did not exhibit any ulceration and showed only a very mild inflammatory infiltrate. In TNF/LT alpha-double ligand0-deficient animals, a moderate epidermal necrosis was observed with a reduced inflammatory infiltrate compared to wild-type animals. As with TNF injections, subcutaneous injection of LPS induced a comparable pattern of skin necrosis in wild-type and TNF receptor mutant mice, yet a slightly more acute inflammatory level was observed regardless of the type of animal tested. As found for TNF-induced skin necrosis, the extent of LPS-induced skin necrosis was reduced in TNF/LT alpha-deficient mice compared to wild-type animals. The present data strongly suggest that TNFR1, rather than TNFR2, is engaged in LPS- and TNF-induced skin necrosis and highlight the predominant role played by TNF in LPS-induced inflammatory diseases.
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PMID:Tumor necrosis factor (TNF)-induced cutaneous necrosis is mediated by TNF receptor 1. 914 75

The effect of a single bolus injection (0.4 g/kg) of intravenous immunoglobulin (IVIG) on the tumor necrosis factor (TNF) system in human immunodeficiency virus type 1 (HIV-1)-infected patients was investigated. At 140 h after infusion, there was a significant decrease in levels of TNF-alpha and a significant increase in levels of soluble TNF receptors (sTNFR) in both plasma and lipopolysaccharide-stimulated peripheral blood mononuclear cells (PBMC). A rapid (within 1 h) decline in expression of membrane-bound TNF-alpha and p55-TNFR on PBMC persisted throughout the study. In contrast, there was an increased expression of membrane-bound p75-TNFR after 140 h. IVIG administration also resulted in significantly increased numbers of circulating CD4 lymphocytes, correlated with down-regulation of TNF-alpha activity in PBMC supernatants. Thus, down-regulation of the abnormally increased TNF-alpha activity may be achieved by IVIG administration. Studies evaluating the possible therapeutic role of long-term TNF-alpha suppression by IVIG may be warranted in HIV-1-infected patients.
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PMID:Effects of intravenous immunoglobulin in vivo on abnormally increased tumor necrosis factor-alpha activity in human immunodeficiency virus type 1 infection. 933 49

Secretion of cytokines by monocytes has been implicated in the pathogenesis of dialysis-related morbidity. Cytokine generation is presumed to take place in two steps: induction of mRNA transcription for cytokines by C5a and direct membrane contact, followed by lipopolysaccharide (LPS)-induced translation of mRNA (priming/second signal theory, Kidney Int 37: 85-93, 1990). However, the in vitro conditions on which this theory was based differed markedly from clinical dialysis. To test this postulate for routine hemodialysis, 13 patients were studied cross-over with high-flux cuprammonium (CU), cellulose triacetate (CTA), and polysulfon dialyzers, using standard bicarbonate dialysate, as well as CTA with filtered dialysate (fCTA). Besides leukocytes, C3a, C5a, and limulus amebocyte lysate reactivity, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-1RA, soluble TNF receptors, and IL-1 beta mRNA were assessed. Only during dialysis with CU did C5a increase significantly (561 to 8185 ng/ml, P < 0.001). Endotoxin content of standard bicarbonate was higher than filtered dialysate (median, 24.3 and < 5 pg/ml respectively, P = 0.002), whereas limulus amebocyte lysate reactivity was not detected in the blood, except in the case of CU. TNF-alpha levels were elevated before, and remained stable during, dialysis, independent of the modality used. IL-1 beta, IL-6, and mRNA coding for IL-1 beta could not be demonstrated. IL-1RA and soluble TNF receptors (p55/p75) were markedly elevated compared with normal control subjects, but showed no differences between fCTA and CTA. To summarize, no evidence was found for production and release of cytokines by monocytes during clinical high-flux bicarbonate hemodialysis, neither with complement-activating membranes nor with unfiltered dialysate. Therefore, this study sheds some doubt on the relevance of the "priming/second signal" theory for clinical practice. The data presented suggest that reluctance to prescribe the use of high-flux dialyzers, as advocated in many reports, may not be warranted.
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PMID:Cytokine profiles during clinical high-flux dialysis: no evidence for cytokine generation by circulating monocytes. 935 78

Sleep is generally enhanced during the early phase of infection. The cytokine tumor necrosis factor (TNF) has been postulated to play an important role in the acute phase sleep response. After demonstrating the ability of a soluble p75 TNF receptor (TNFR) to inhibit TNF activity in vitro, we assessed the influence of TNFR on the sleep changes evoked by lipopolysaccharide (LPS). In this vehicle-controlled experiment, 24 rats received either an intracerebroventricular injection of 10 micrograms TNFR, an intraperitoneal injection of 30 micrograms/kg LPS, or both, at the beginning of the dark period. EEG, EMG and brain temperature (Tbr) were recorded during the first 12 h post injection. Compared with vehicle, LPS had minimal effects on Tbr, but promoted non-rapid eye movement sleep (non-REMS), suppressed REMS, shortened the sleep episodes and decreased high-frequency (> or = 8 Hz) EEG activity during non-REMS. TNFR alone had no significant effects and did not attenuate any of the LPS-induced sleep changes. These results may either indicate that TNF is not critically involved in the sleep response to a low level LPS challenge during the activity phase or that the soluble p75 TNFR does not effectively antagonize the sleep changes evoked by TNF.
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PMID:Soluble tumor necrosis factor receptor (p75) does not attenuate the sleep changes induced by lipopolysaccharide in the rat during the dark period. 937 18

PGG-Glucan (Betafectin) is a novel soluble beta-glucan immunomodulator that enhances leukocyte microbicidal activities without inducing inflammatory cytokines. Although several different receptors for soluble and particulate beta-glucans have been described, the signal transduction pathway(s) used by soluble beta-glucans have not been elucidated. We report that in a murine monocytic cell line (BMC2.3) PGG-Glucan activates nuclear factor-kappaB (NF-kappaB)-like and NF-interleukin-6 (IL-6)-like transcription factors. Electrophoretic mobility shift assays showed that PGG-Glucan activation of the factors is time- and concentration-dependent. The NF-kappaB-like complex includes subunit p65 (rel-A) as one of its components, but apparently not p50 (kappaB1), p52 (kappaB2), p68 (rel-B), or p75 (C-rel) family members. The NF-IL-6-like complex contains subunit C/EBP-beta (NF-IL-6alpha) as one of its components, but apparently not C/EBP-alpha or C/EBP-delta (NF-IL-6beta). As expected, lipopolysaccharide (LPS) activated p65/p50 NF-kappaB and C/EBP-beta NF-IL-6 complexes, increased the nuclear titer of p65 and p50 antigens, and increased cytokine (IL-1beta, tumor necrosis factor alpha) mRNA production. In contrast, PGG-Glucan increased the nuclear titer of p65, but apparently not p50, and did not induce cytokine mRNA production. These data demonstrate that PGG-Glucan utilizes signal transduction pathways different from those used by LPS. The data suggest that activation of the PGG-Glucan-stimulated factors is not sufficient to stimulate cytokine mRNA transcription.
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PMID:PGG-Glucan activates NF-kappaB-like and NF-IL-6-like transcription factor complexes in a murine monocytic cell line. 940 Aug 29

Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the host's immunomodulatory response to infective agents. To evaluate the TNF-alpha system in patients with chronic hepatitis C virus (HCV) infection, plasma, serum, and peripheral blood mononuclear cells (PBMC) were prospectively collected from 53 patients and 33 healthy control subjects. Circulating TNF-alpha and TNF receptors were assayed by their respective enzyme immunoassays. In addition, TNF-alpha mRNA was quantitated in PBMC using a branched DNA assay, and production of TNF-alpha by PBMC with and without lipopolysaccharide was also assessed. Patients with chronic HCV infection had a higher level of circulating TNF-alpha compared to healthy control subjects (9.62 +/- 6.01 vs 3.66 +/- 1.23 pg/ml, P < 0.001). They also had higher circulating levels of TNF receptors compared to control (CD120a: 3323 +/- 1267, pg/ml, N = 49 vs 1855 +/- 422 pg/ml, N = 33, P < 0.001; CD120b: 1290 +/- 650 pg/ml, N = 51, vs 863 +/- 207 pg/ml, N = 33, P < 0.001). Plasma TNF-alpha level correlated with circulating CD120a (r = 0.52, N = 49, P < 0.001) and weakly with CD120b (r = 0.32, N = 51, P = 0.02). Plasma TNF-alpha also correlated with markers of hepatocellular injury, including ALT (r = 0.34, N = 53, P = 0.01) and alpha-GST (r = 0.31, N = 43, P = 0.042), but not with serum HCV RNA levels. There was no difference in the TNF-alpha mRNA levels in PBMC between patients with chronic HCV infection (1.4 +/- 1.9 units/10[6] cells, N = 8) and healthy control subjects (2.1 +/- 1.4 units/10[6] cells, N = 8, P = NS). There was also no difference in the spontaneous production of TNF-alpha by PBMC (1 x 10[6] cells/ml) between patients with chronic HCV infection (14.2 +/- 36.5 pg/ml, N = 11) and healthy subjects (11.9 +/- 14.0 pg/ml, N = 14, P = NS). However, patients with chronic HCV infection produced more TNF-alpha upon stimulation with lipopolysaccharide compared to healthy control subjects (1278 +/- 693 pg/ml, N = 11, vs 629 +/- 689 pg/ml, N = 14, P < 0.05). These data indicate that the TNF-alpha system is activated in patients with chronic HCV infection.
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PMID:Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection. 944 Jun 25


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