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 studied the effect of corticosterone on interleukin (IL)-1 beta synthesis, body temperature, general activity, food consumption and fluid intake in rats treated with bacterial lipopolysaccharide (LPS). Radiotelemetry was used to assess body temperature and locomotor activity in combination with continuous automated recordings of feeding and drinking. This technique was developed as a novel method to identify and measure sickness behavior in rodents. The animals were (a) sham-operated, (b) adrenalectomized or (c) sham-operated and treated with corticosterone (10 mg/kg, subcutaneously). They were then intraperitoneally injected with vehicle or LPS at a dose (100 micrograms/kg) that in sham-operated rats induced fever and anorexia, reduced spontaneous activity and increased IL1-beta mRNA in spleen and adrenals as determined by Northern blot analysis. Adrenalectomized rats produced larger amounts of splenic IL-1 beta mRNA, reduced their general activity much more and developed a mild adipsia as compared with adrenal-intact animals. Administration of corticosterone 1 h before LPS lowered the splenic IL-1 beta mRNA content compared to LPS-treated adrenal-intact rats that did not receive corticosterone and inhibited fever and anorexia, whereas the glucocorticoid did not attenuate the endotoxin-induced suppression of locomotor activity. Our data suggest that during inflammatory conditions body temperature, sickness behavior and the synthesis of IL-1 beta are controlled by corticosterone. Different components of sickness behavior seem to be independently regulated and are under differential control by glucocorticoids.
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PMID:Corticosterone controls interleukin-1 beta expression and sickness behavior in the rat. 886 60

The activities of interleukin-1 alpha(IL-1 alpha) and interleukin-1 beta (IL-1 beta) were investigated in whole-blood cultures from 30 patients with bladder cancer and 16 healthy subjects. Heparinized blood was cultured in the absence and presence of various concentrations of bacterial lipopolysaccharide (LPS). The culture supernatants were obtained and the activities of IL-1 alpha and IL-1 beta determined by enzyme-linked immunosorbent assay (ELISA). In the absence of LPS stimulation, there was no significant spontaneous elaboration of IL-1 alpha and IL-1 beta in patients with bladder cancer compared with control subjects. Under the stimulation of various concentrations of LPS, patients with bladder cancer and controls subjects produced IL-1 alpha and IL-1 beta in a dose-dependent manner, and IL-1 beta was found predominantly in the supernatant. Lower IL-1 alpha and higher IL-1 beta activities were found in patients with bladder cancer, but statistical significance was not achieved when compared with control subjects. This study suggested that patients with bladder cancer have no spontaneous elaboration of IL-1 alpha and IL-1 beta and no significant impaired ability in LPS-stimulated IL-1 alpha and IL1 beta production.
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PMID:An assessment of interleukin-1 alpha and interleukin-1 beta production in patients with bladder cancer. 892 Jul 68

Incubation of C6 astrocytoma cells with bacterial endotoxin (lipopolysaccharide; LPS) plus interferon-gamma (IFN-gamma), or with a combination of cytokines (TNF-alpha, IL1-beta, and IFN-gamma) leads to high levels of inducible nitric oxide synthase (iNOS) expression. Previous results demonstrated a requirement for tyrosine kinase (TK) activities for iNOS induction. In the present study, a set of structurally related TK inhibitors, the tyrphostins (TYRs), were used to characterize possible differences between LPS and cytokine iNOS induction. All TYRs tested suppressed both types of induction. However, dose-response curves revealed significant differences in the IC50 values obtained for some TYRs (T25 and T56), and significant differences in the IC50 potency rank order when comparing inhibition of LPS versus cytokine-dependent iNOS induction. These results are consistent with differential TK utilization by the LPS versus cytokine pathways of iNOS induction, and establish a basis for developing further selective inhibitors of iNOS expression.
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PMID:Differential suppression of glial nitric oxide synthase induction by structurally related tyrosine kinase inhibitors. 906 10

Several experimental findings suggest a potential role of excessive nitric oxide (NO) production by macrophages, microglia and astrocytes in the pathogenesis of demyelinating lesions in MS. We assessed the production of nitrites by peripheral blood mononuclear cells (PBMCs) of 15 MS patients (10 F and 5 M) with the R-R form (EDSS: 1-3.0) and in 15 age-matched control subjects. 9 out of the 15 MS patients showed active lesions in MRI at the time of examination. 7 patients were also monitored at the onset, during and following a clinical relapse. Secretion of cytokines by PBMCs was assessed at the basal time and after 24 h of incubation with lipopolysaccharide (LPS). The production of nitrites in the supernatants of PBMCs stimulated and not stimulated with lipopolysaccharide was evaluated. The secretion of IL1 beta, IFN-gamma, TNF-alpha, IL-6 IL-10 and TGF-beta by PBMCs was detected using ELISA methods. The production of NO, both basal and stimulated, was significantly higher in the patients with active lesions than in those without active lesions (p < 0.01). No significant difference was evident between the basal and LPS-stimulated production of NO between control subjects and MS patients without active lesions. During relapses there was a significant increase in NO production by PBMCs compared to the clinical stable stage of the disease (p < 0.0001). This increase was significantly greater in the early stage of relapse than in the late stage (p < 0.04). A decline of NO levels was observed during recovery. Steroid treatment induced a significant decrease in the PBMC NO production of MS patients during exacerbations (p < 0.01). The levels of IL-1 beta, IFN-gamma and TNF-alpha are significantly higher in the supernatants of the PBMCs which produced greater amounts of NO (p < 0.02, p < 0.03, p < 0.01, respectively). On the other hand, NO levels were negatively related to IL-10 and TGF-beta production (R = -75, p < 0.0001 and R = -0.79, p < 0.0001, respectively). The increase production of NO by peripheral blood mononuclear cells demonstrated in our study to be associated with increased production of proinflammatory cytokines could therefore be considered to be a marker of mononuclear cell activation in the peripheral blood of MS patients and, indirectly, of disease activity. Its increased secretion during T cell and monocyte homing in the CNF could contribute to the damage to the blood-brain barrier and the subsequent cytokine-mediated cytotoxic effect to myelin and oligodendrocytes in the white matter of MS patients.
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PMID:Cytokine secretion and nitric oxide production by mononuclear cells of patients with multiple sclerosis. 941 61

Rat C6 glioma cells were stably transfected with a human cDNA encoding heat shock protein (HSP)70. Immunostaining revealed the presence of largely cytosolic HSP70 in C6-hsp70 cells, but not in control (vector transfected) C6-pTK cells. Induction of nitric oxide synthase (NOS-2) expression in C6-hsp70 cells, assessed by nitrite accumulation, was significantly reduced compared to control C6-pTK cells (25+/-8% of control cell induction, P < 0.005), when induced with a maximally stimulatory combination of bacterial endotoxin lipopolysaccharide (LPS) plus a mixture of three cytokines ("CM:" TNF-alpha, IL1-beta, and IFN-gamma). Immunostaining for the transcription factor NFkappaB p65 subunit revealed decreased cytokine-dependent nuclear uptake in HSP70 expressing cells compared to control cells. Activation of C6 cell NFkappaB by LPS plus CM required IkappaB degradation by the 20S proteasome, since NOS-2 expression was blocked by a selective proteasome inhibitor. In parental C6 cells, the presence of LPS plus CM caused a rapid (within 30 min) decrease in inhibitory IkappaB-alpha protein levels, and this loss was abolished by prior heat shock of the cells. In contrast, IkappaB-alpha levels in transfected cells were not modified by the expression of HSP70. These results demonstrate that constitutive HSP70 expression in glial cells can reduce NOS-2 induction, presumably due to inhibition of NFkappaB nuclear uptake. Furthermore, whereas prevention of decreases in IkappaB-alpha can account for the suppressive effects of heat shock, the results suggest that HSP70 blocks NOS-2 induction by interfering at a later step in the NFkappaB activation pathway.
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PMID:Suppression of glial nitric oxide synthase induction by heat shock: effects on proteolytic degradation of IkappaB-alpha. 970 Oct 55

Polymorphonuclear neutrophils are the predominant cells in acute inflammatory lesions and their functions and recruitment are regulated by cytokines, including IL1, TNF and IL8. Antibiotic modulation of inflammatory effects has stimulated investigations of antibiotics for their potential activity as immunomodulators over their primary bactericidal or bacteriostatic activities. This study reports the influence of macrolides, spiramycin and dirithromycin on IL1 beta production. Mononuclear cells, isolated from healthy human volunteers, were preincubated with macrolides (0.1 to 500 micrograms/ml) and stimulated by Escherichia coli lipopolysaccharide. Then, IL1 beta production was detected by western blotting analysis. At therapeutic concentrations, dirithromycin and spiramycin seemed to enhance IL1 beta production by LPS-stimulated cells, with +37 per cent and +28 per cent at 1 microgram/ml respectively. At supratherapeutic concentrations, these drugs seemed to inhibit IL1 beta production through protein kinase C inhibition, with inhibitory concentrations 50 per cent of 378 micrograms/ml for dirithromycin and 234 micrograms/ml for spiramycin. So, macrolides may modulate the host defence system through their influence on cytokine production.
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PMID:In vitro effects of spiramycin and dirithromycin on IL1 beta production by human LPS-stimulated mononuclear cells. 1066 98

The etiology of Parkinson's disease is not known. Nevertheless a significant body of biochemical data from human brain autopsy studies and those from animal models point to an on going process of oxidative stress in the substantia nigra which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Nevertheless, oxidative stress as induced by neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been used in animal models to investigate the process of neurodegeneration with intend to develop antioxidant neuroprotective drugs. It is apparent that in these animal models radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists do induce neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided also evidence for an inflammatory process. This expresses itself by proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors, NF kappa-beta and elevation of cytotoxic cytokines TNF alpha, IL1-beta, and IL6. Both radical scavengers and iron chelators prevent LPS (lipopolysaccharide) and iron induced activation of NF kappa-B. If an inflammatory response is involved in Parkinson's disease it would be logical to consider antioxidants and the newly developed non-steroid anti-inflammatory drugs such as COX2 (cyclo-oxygenase) inhibitors as a form of treatment. However to date there has been little or no success in the clinical treatment of neurodegenerative diseases per se (Parkinson's disease, ischemia etc.), where neurons die, while in animal models the same drugs produce neuroprotection. This may indicate that either the animal models employed are not reflective of the events in neurodegenerative diseases or that because neuronal death involves a cascade of events, a single neuroprotective drug would not be effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
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PMID:Neuroprotective strategies in Parkinson's disease using the models of 6-hydroxydopamine and MPTP. 1086 45

We have shown previously that febrile range temperatures modify cytokine production by adult macrophages. In this study, we compared the effects of moderate hyperthermia and hypothermia on the kinetics of lipopolysaccharide (LPS)-induced cytokine expression in monocytes and macrophages of newborns and adults. During culture at 40 degrees C, the initial rates of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion were preserved, but the duration of secretion was shorter than the duration at 37 degrees C. TNF-alpha and IL1-beta concentrations in 24-h 40 degrees C culture supernatants were reduced 18%-50%. IL-6 concentration in 24-h 40 degrees C cultures was reduced 26%-29% in all cells except adult macrophages. At 32 degrees C, changes in early (2 h) and sustained (24 h) cytokine expression were reversed compared with those caused by hyperthermia. Culturing adult macrophages at 32 degrees C blunted early secretion of TNF-alpha and IL-6 by 69% and 65%, respectively, and increased TNF-alpha concentration at 24 h by 48% compared with levels at 37 degrees C. In adult monocytes cultured at 32 degrees C, early IL-6 and IL-1 beta secretion was decreased 64% and 51%, respectively. We speculate that the burst/suppression cytokine profile at febrile temperatures might enhance early activation of host defenses and prevent prolonged exposure to potentially cytotoxic cytokines. Hypothermia, on the other hand, may worsen outcome in infections by delaying and prolonging cytokine production.
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PMID:Effects of hypothermia and hyperthermia on cytokine production by cultured human mononuclear phagocytes from adults and newborns. 1115 70

The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovascular hormone which possesses well defined natriuretic, diuretic, and vasodilating properties. Most of the biological effects of ANP aremediated through its guanylyl cyclase coupled A receptor. Because ANP and its receptors have been shown to be expressed and differentially regulated in the immune system, it has been suggested that ANP has an immunomodulatory potency. Much investigation of the effects of ANP on the activation of macrophages has been carried out. ANP was shown to inhibit the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in macrophages in an autocrine fashion. ANP in this context was shown to reduce significantly the activation of NF-kappaB and to destabilise iNOS mRNA. ANP, furthermore, can significantly reduce the LPS-induced secretion of tumour necrosis factor alpha (TNFalpha) in macrophages. The relevance of these findings on a regulatory role for ANP on TNFalpha in humans was shown by the fact that ANP significantly reduces the release of TNFalpha in whole human blood. It was furthermore shown to attenuate the release of interleukin 1beta (IL1beta). Interestingly, ANP did not affect the secretion of the anti-inflammatory cytokines IL10 and IL1 receptor antagonist (IL1ra). In summary, ANP was shown to reduce the secretion of inflammatory mediators in macrophages. Therefore, this cardiovascular hormone may possess anti-inflammatory potential.
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PMID:The atrial natriuretic peptide regulates the production of inflammatory mediators in macrophages. 1189 Jun 59

In mammalian cells, RNA duplexes of 21-23 nucleotides, known as small interfering RNAs (siRNAs) specifically inhibit gene expression in vitro. Here, we show that systemic delivery of siRNAs can inhibited exogenous and endogenous gene expression in adult mice. Cationic liposome-based intravenous injection in mice of plasmid encoding the green fluorescent protein (GFP) with its cognate siRNA, inhibited GFP gene expression in various organs. Furthermore, intraperitoneal injection of anti-TNF-alpha siRNA inhibited lipopolysaccharide-induced TNF-alpha gene expression, whereas secretion of IL1-alpha was not inhibited. Importantly, the development of sepsis in mice following a lethal dose of lipopolysaccharide injection, was significantly inhibited by pre-treatment of the animals with anti-TNF-alpha siRNAs. Collectively, these results demonstrate that synthetic siRNAs can function in vivo as pharmaceutical drugs.
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PMID:Gene silencing by systemic delivery of synthetic siRNAs in adult mice. 1265 61


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